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Generation and degradation of free asparagine-linked glycans

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Abstract

Asparagine (N)-linked protein glycosylation, which takes place in the eukaryotic endoplasmic reticulum (ER), is important for protein folding, quality control and the intracellular trafficking of secretory and membrane proteins. It is known that, during N-glycosylation, considerable amounts of lipid-linked oligosaccharides (LLOs), the glycan donor substrates for N-glycosylation, are hydrolyzed to form free N-glycans (FNGs) by unidentified mechanisms. FNGs are also generated in the cytosol by the enzymatic deglycosylation of misfolded glycoproteins during ER-associated degradation. FNGs derived from LLOs and misfolded glycoproteins are eventually merged into one pool in the cytosol and the various glycan structures are processed to a near homogenous glycoform. This article summarizes the current state of our knowledge concerning the formation and catabolism of FNGs.

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References

  1. Kelleher DJ, Gilmore R (2006) An evolving view of the eukaryotic oligosaccharyltransferase. Glycobiology 16(4):47R–62R. doi:10.1093/glycob/cwj066

    CAS  PubMed  Google Scholar 

  2. Aebi M (2013) N-linked protein glycosylation in the ER. Biochim Biophys Acta 1833(11):2430–2437. doi:10.1016/j.bbamcr.2013.04.001

    CAS  PubMed  Google Scholar 

  3. Apweiler R, Hermjakob H, Sharon N (1999) On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta 1473(1):4–8

    CAS  PubMed  Google Scholar 

  4. Winchester B (2005) Lysosomal metabolism of glycoproteins. Glycobiology 15(6):1R–15R. doi:10.1093/glycob/cwi041

    CAS  PubMed  Google Scholar 

  5. Funakoshi Y, Suzuki T (2009) Glycobiology in the cytosol: the bitter side of a sweet world. Biochim Biophys Acta 1790(2):81–94. doi:10.1016/j.bbagen.2008.09.009

    CAS  PubMed  Google Scholar 

  6. Suzuki T, Harada Y (2014) Non-lysosomal degradation pathway for N-linked glycans and dolichol-linked oligosaccharides. Biochem Biophys Res Commun 453(2):213–219. doi:10.1016/j.bbrc.2014.05.075

    CAS  PubMed  Google Scholar 

  7. Suzuki T, Funakoshi Y (2006) Free N-linked oligosaccharide chains: formation and degradation. Glycoconj J 23(5–6):291–302. doi:10.1007/s10719-006-6975-x

    CAS  PubMed  Google Scholar 

  8. Barnes G, Hansen WJ, Holcomb CL, Rine J (1984) Asparagine-linked glycosylation in Saccharomyces cerevisiae: genetic analysis of an early step. Mol Cell Biol 4(11):2381–2388

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Wu X, Rush JS, Karaoglu D, Krasnewich D, Lubinsky MS, Waechter CJ, Gilmore R, Freeze HH (2003) Deficiency of UDP-GlcNAc: dolichol phosphate N-Acetylglucosamine-1 phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation Type Ij. Hum Mutat 22(2):144–150. doi:10.1002/humu.10239

    CAS  PubMed  Google Scholar 

  10. Gao XD, Moriyama S, Miura N, Dean N, Nishimura S (2008) Interaction between the C termini of Alg13 and Alg14 mediates formation of the active UDP-N-acetylglucosamine transferase complex. J Biol Chem 283(47):32534–32541. doi:10.1074/jbc.M804060200

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Gao XD, Tachikawa H, Sato T, Jigami Y, Dean N (2005) Alg14 recruits Alg13 to the cytoplasmic face of the endoplasmic reticulum to form a novel bipartite UDP-N-acetylglucosamine transferase required for the second step of N-linked glycosylation. J Biol Chem 280(43):36254–36262. doi:10.1074/jbc.M507569200

    CAS  PubMed  Google Scholar 

  12. Bickel T, Lehle L, Schwarz M, Aebi M, Jakob CA (2005) Biosynthesis of lipid-linked oligosaccharides in Saccharomyces cerevisiae: Alg13p and Alg14p form a complex required for the formation of GlcNAc(2)-PP-dolichol. J Biol Chem 280(41):34500–34506. doi:10.1074/jbc.M506358200

    CAS  PubMed  Google Scholar 

  13. Bissar-Tadmouri N, Donahue WL, Al-Gazali L, Nelson SF, Bayrak-Toydemir P, Kantarci S (2014) X chromosome exome sequencing reveals a novel ALG13 mutation in a nonsyndromic intellectual disability family with multiple affected male siblings. Am J Med Genet A 164A(1):164–169

    PubMed  Google Scholar 

  14. Cossins J, Belaya K, Hicks D, Salih MA, Finlayson S, Carboni N, Liu WW, Maxwell S, Zoltowska K, Farsani GT, Laval S, Seidhamed MZ, Donnelly P, Bentley D, McGowan SJ, Muller J, Palace J, Lochmuller H, Beeson D (2013) Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain 136(Pt 3):944–956. doi:10.1093/brain/awt010

    PubMed Central  PubMed  Google Scholar 

  15. Schwarz M, Thiel C, Lubbehusen J, Dorland B, de Koning T, von Figura K, Lehle L, Korner C (2004) Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik. Am J Hum Genet 74(3):472–481. doi:10.1086/382492

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Huffaker TC, Robbins PW (1982) Temperature-sensitive yeast mutants deficient in asparagine-linked glycosylation. J Biol Chem 257(6):3203–3210

    CAS  PubMed  Google Scholar 

  17. Couto JR, Huffaker TC, Robbins PW (1984) Cloning and expression in Escherichia coli of a yeast mannosyltransferase from the asparagine-linked glycosylation pathway. J Biol Chem 259(1):378–382

    CAS  PubMed  Google Scholar 

  18. Thiel C, Schwarz M, Peng J, Grzmil M, Hasilik M, Braulke T, Kohlschutter A, von Figura K, Lehle L, Korner C (2003) A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. J Biol Chem 278(25):22498–22505. doi:10.1074/jbc.M302850200

    CAS  PubMed  Google Scholar 

  19. Huffaker TC, Robbins PW (1983) Yeast mutants deficient in protein glycosylation. Proc Natl Acad Sci USA 80(24):7466–7470

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Rind N, Schmeiser V, Thiel C, Absmanner B, Lubbehusen J, Hocks J, Apeshiotis N, Wilichowski E, Lehle L, Korner C (2010) A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11 leads to congenital disorder of glycosylation-Ip. Hum Mol Genet 19(8):1413–1424. doi:10.1093/hmg/ddq016

    CAS  PubMed  Google Scholar 

  21. Cipollo JF, Trimble RB, Chi JH, Yan Q, Dean N (2001) The yeast ALG11 gene specifies addition of the terminal alpha 1,2-Man to the Man5GlcNAc2-PP-dolichol N-glycosylation intermediate formed on the cytosolic side of the endoplasmic reticulum. J Biol Chem 276(24):21828–21840. doi:10.1074/jbc.M010896200

    CAS  PubMed  Google Scholar 

  22. Valderrama-Rincon JD, Fisher AC, Merritt JH, Fan YY, Reading CA, Chhiba K, Heiss C, Azadi P, Aebi M, DeLisa MP (2012) An engineered eukaryotic protein glycosylation pathway in Escherichia coli. Nat Chem Biol 8(5):434–436. doi:10.1038/nchembio.921

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Helenius J, Ng DT, Marolda CL, Walter P, Valvano MA, Aebi M (2002) Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein. Nature 415(6870):447–450. doi:10.1038/415447a

    CAS  PubMed  Google Scholar 

  24. Frank CG, Sanyal S, Rush JS, Waechter CJ, Menon AK (2008) Does Rft1 flip an N-glycan lipid precursor? Nature 454(7204):E3–E4. doi:10.1038/nature07165 (discussion E4–E5)

    CAS  PubMed  Google Scholar 

  25. Rush JS, Gao N, Lehrman MA, Matveev S, Waechter CJ (2009) Suppression of Rft1 expression does not impair the transbilayer movement of Man5GlcNAc2-P-P-dolichol in sealed microsomes from yeast. J Biol Chem 284(30):19835–19842. doi:10.1074/jbc.M109.000893

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Sanyal S, Menon AK (2009) Specific transbilayer translocation of dolichol-linked oligosaccharides by an endoplasmic reticulum flippase. Proc Natl Acad Sci USA 106(3):767–772. doi:10.1073/pnas.0810225106

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Schollen E, Grunewald S, Keldermans L, Albrecht B, Korner C, Matthijs G (2005) CDG-Id caused by homozygosity for an ALG3 mutation due to segmental maternal isodisomy UPD3(q21.3-qter). Eur J Med Genet 48(2):153–158. doi:10.1016/j.ejmg.2005.01.002

    CAS  PubMed  Google Scholar 

  28. Aebi M, Gassenhuber J, Domdey H, te Heesen S (1996) Cloning and characterization of the ALG3 gene of Saccharomyces cerevisiae. Glycobiology 6(4):439–444

    CAS  PubMed  Google Scholar 

  29. Frank CG, Grubenmann CE, Eyaid W, Berger EG, Aebi M, Hennet T (2004) Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL. Am J Hum Genet 75(1):146–150. doi:10.1086/422367

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Burda P, te Heesen S, Brachat A, Wach A, Dusterhoft A, Aebi M (1996) Stepwise assembly of the lipid-linked oligosaccharide in the endoplasmic reticulum of Saccharomyces cerevisiae: identification of the ALG9 gene encoding a putative mannosyl transferase. Proc Natl Acad Sci USA 93(14):7160–7165

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Cipollo JF, Trimble RB (2002) The Saccharomyces cerevisiae alg12∆ mutant reveals a role for the middle-arm α1,2Man- and upper-arm α1,2Manα1,6Man- residues of Glc3Man9GlcNAc2-PP-Dol in regulating glycoprotein glycan processing in the endoplasmic reticulum and Golgi apparatus. Glycobiology 12(11):749–762

    CAS  PubMed  Google Scholar 

  32. Grubenmann CE, Frank CG, Kjaergaard S, Berger EG, Aebi M, Hennet T (2002) ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg. Hum Mol Genet 11(19):2331–2339

    CAS  PubMed  Google Scholar 

  33. Chantret I, Dupre T, Delenda C, Bucher S, Dancourt J, Barnier A, Charollais A, Heron D, Bader-Meunier B, Danos O, Seta N, Durand G, Oriol R, Codogno P, Moore SE (2002) Congenital disorders of glycosylation type Ig is defined by a deficiency in dolichyl-P-mannose:Man7GlcNAc2-PP-dolichyl mannosyltransferase. J Biol Chem 277(28):25815–25822. doi:10.1074/jbc.M203285200

    CAS  PubMed  Google Scholar 

  34. Burda P, Jakob CA, Beinhauer J, Hegemann JH, Aebi M (1999) Ordered assembly of the asymmetrically branched lipid-linked oligosaccharide in the endoplasmic reticulum is ensured by the substrate specificity of the individual glycosyltransferases. Glycobiology 9(6):617–625

    CAS  PubMed  Google Scholar 

  35. Imbach T, Burda P, Kuhnert P, Wevers RA, Aebi M, Berger EG, Hennet T (1999) A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic. Proc Natl Acad Sci USA 96(12):6982–6987

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Reiss G, te Heesen S, Zimmerman J, Robbins PW, Aebi M (1996) Isolation of the ALG6 locus of Saccharomyces cerevisiae required for glucosylation in the N-linked glycosylation pathway. Glycobiology 6(5):493–498

    CAS  PubMed  Google Scholar 

  37. Chantret I, Dancourt J, Dupre T, Delenda C, Bucher S, Vuillaumier-Barrot S, Ogier de Baulny H, Peletan C, Danos O, Seta N, Durand G, Oriol R, Codogno P, Moore SE (2003) A deficiency in dolichyl-P-glucose:Glc1Man9GlcNAc2-PP-dolichyl α3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation. J Biol Chem 278(11):9962–9971. doi:10.1074/jbc.M211950200

    CAS  PubMed  Google Scholar 

  38. Stagljar I, te Heesen S, Aebi M (1994) New phenotype of mutations deficient in glucosylation of the lipid-linked oligosaccharide: cloning of the ALG8 locus. Proc Natl Acad Sci USA 91(13):5977–5981

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Burda P, Aebi M (1998) The ALG10 locus of Saccharomyces cerevisiae encodes the alpha-1,2 glucosyltransferase of the endoplasmic reticulum: the terminal glucose of the lipid-linked oligosaccharide is required for efficient N-linked glycosylation. Glycobiology 8(5):455–462

    CAS  PubMed  Google Scholar 

  40. Rush JS, Cho SK, Jiang S, Hofmann SL, Waechter CJ (2002) Identification and characterization of a cDNA encoding a dolichyl pyrophosphate phosphatase located in the endoplasmic reticulum of mammalian cells. J Biol Chem 277(47):45226–45234. doi:10.1074/jbc.M207076200

    CAS  PubMed  Google Scholar 

  41. Fernandez F, Rush JS, Toke DA, Han GS, Quinn JE, Carman GM, Choi JY, Voelker DR, Aebi M, Waechter CJ (2001) The CWH8 gene encodes a dolichyl pyrophosphate phosphatase with a luminally oriented active site in the endoplasmic reticulum of Saccharomyces cerevisiae. J Biol Chem 276(44):41455–41464. doi:10.1074/jbc.M105544200

    CAS  PubMed  Google Scholar 

  42. van Berkel MA, Rieger M, te Heesen S, Ram AF, van den Ende H, Aebi M, Klis FM (1999) The Saccharomyces cerevisiae CWH8 gene is required for full levels of dolichol-linked oligosaccharides in the endoplasmic reticulum and for efficient N-glycosylation. Glycobiology 9(3):243–253

    PubMed  Google Scholar 

  43. Rush JS, Gao N, Lehrman MA, Waechter CJ (2008) Recycling of dolichyl monophosphate to the cytoplasmic leaflet of the endoplasmic reticulum after the cleavage of dolichyl pyrophosphate on the lumenal monolayer. J Biol Chem 283(7):4087–4093. doi:10.1074/jbc.M707067200

    CAS  PubMed  Google Scholar 

  44. Chavan M, Yan A, Lennarz WJ (2005) Subunits of the translocon interact with components of the oligosaccharyl transferase complex. J Biol Chem 280(24):22917–22924. doi:10.1074/jbc.M502858200

    CAS  PubMed  Google Scholar 

  45. Yan A, Lennarz WJ (2005) Two oligosaccharyl transferase complexes exist in yeast and associate with two different translocons. Glycobiology 15(12):1407–1415. doi:10.1093/glycob/cwj026

    CAS  PubMed  Google Scholar 

  46. Harada Y, Li H, Lennarz WJ (2009) Oligosaccharyltransferase directly binds to ribosome at a location near the translocon-binding site. Proc Natl Acad Sci USA 106(17):6945–6949. doi:10.1073/pnas.0812489106

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Ruiz-Canada C, Kelleher DJ, Gilmore R (2009) Cotranslational and posttranslational N-glycosylation of polypeptides by distinct mammalian OST isoforms. Cell 136(2):272–283. doi:10.1016/j.cell.2008.11.047

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Shibatani T, David LL, McCormack AL, Frueh K, Skach WR (2005) Proteomic analysis of mammalian oligosaccharyltransferase reveals multiple subcomplexes that contain Sec61, TRAP, and two potential new subunits. Biochemistry 44(16):5982–5992. doi:10.1021/bi047328f

    CAS  PubMed  Google Scholar 

  49. Pfeffer S, Dudek J, Gogala M, Schorr S, Linxweiler J, Lang S, Becker T, Beckmann R, Zimmermann R, Forster F (2014) Structure of the mammalian oligosaccharyl-transferase complex in the native ER protein translocon. Nat Commun 5:3072. doi:10.1038/ncomms4072

    PubMed  Google Scholar 

  50. Lau JT, Welply JK, Shenbagamurthi P, Naider F, Lennarz WJ (1983) Substrate recognition by oligosaccharyl transferase. Inhibition of co-translational glycosylation by acceptor peptides. J Biol Chem 258(24):15255–15260

    CAS  PubMed  Google Scholar 

  51. Duvet S, Op De Beeck A, Cocquerel L, Wychowski C, Cacan R, Dubuisson J (2002) Glycosylation of the hepatitis C virus envelope protein E1 occurs posttranslationally in a mannosylphosphoryldolichol-deficient CHO mutant cell line. Glycobiology 12(2):95–101

    CAS  PubMed  Google Scholar 

  52. Nilsson IM, von Heijne G (1993) Determination of the distance between the oligosaccharyltransferase active site and the endoplasmic reticulum membrane. J Biol Chem 268(8):5798–5801

    CAS  PubMed  Google Scholar 

  53. Li H, Chavan M, Schindelin H, Lennarz WJ (2008) Structure of the oligosaccharyl transferase complex at 12 A resolution. Structure 16(3):432–440. doi:10.1016/j.str.2007.12.013

    CAS  PubMed  Google Scholar 

  54. Lizak C, Gerber S, Numao S, Aebi M, Locher KP (2011) X-ray structure of a bacterial oligosaccharyltransferase. Nature 474(7351):350–355. doi:10.1038/nature10151

    CAS  PubMed  Google Scholar 

  55. Welply JK, Shenbagamurthi P, Lennarz WJ, Naider F (1983) Substrate recognition by oligosaccharyltransferase. Studies on glycosylation of modified Asn-X-Thr/Ser tripeptides. J Biol Chem 258(19):11856–11863

    CAS  PubMed  Google Scholar 

  56. Karaoglu D, Kelleher DJ, Gilmore R (2001) Allosteric regulation provides a molecular mechanism for preferential utilization of the fully assembled dolichol-linked oligosaccharide by the yeast oligosaccharyltransferase. Biochemistry 40(40):12193–12206

    CAS  PubMed  Google Scholar 

  57. Kelleher DJ, Karaoglu D, Mandon EC, Gilmore R (2003) Oligosaccharyltransferase isoforms that contain different catalytic STT3 subunits have distinct enzymatic properties. Mol Cell 12(1):101–111

    CAS  PubMed  Google Scholar 

  58. Sharma CB, Lehle L, Tanner W (1981) N-Glycosylation of yeast proteins. Characterization of the solubilized oligosaccharyl transferase. Eur J Biochem 116(1):101–108

    CAS  PubMed  Google Scholar 

  59. Breuer W, Bause E (1995) Oligosaccharyl transferase is a constitutive component of an oligomeric protein complex from pig liver endoplasmic reticulum. Eur J Biochem 228(3):689–696

    CAS  PubMed  Google Scholar 

  60. Frank CG, Aebi M (2005) ALG9 mannosyltransferase is involved in two different steps of lipid-linked oligosaccharide biosynthesis. Glycobiology 15(11):1156–1163. doi:10.1093/glycob/cwj002

    CAS  PubMed  Google Scholar 

  61. Isono T (2011) O-GlcNAc-specific antibody CTD110.6 cross-reacts with N-GlcNAc2-modified proteins induced under glucose deprivation. PLoS ONE 6(4):e18959. doi:10.1371/journal.pone.0018959

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Isono T, Chano T, Okabe H, Suzaki M (2013) Study of global transcriptional changes of N-GlcNAc2 proteins-producing T24 bladder carcinoma cells under glucose deprivation. PLoS ONE 8(4):e60397. doi:10.1371/journal.pone.0060397

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Isono T, Chano T, Kitamura A, Yuasa T (2014) Glucose deprivation induces G2/M transition-arrest and cell death in N-GlcNAc2-modified protein-producing renal carcinoma cells. PLoS ONE 9(5):e96168. doi:10.1371/journal.pone.0096168

    PubMed Central  PubMed  Google Scholar 

  64. Berriman M, Ghedin E, Hertz-Fowler C, Blandin G, Renauld H, Bartholomeu DC, Lennard NJ, Caler E, Hamlin NE, Haas B, Bohme U, Hannick L, Aslett MA, Shallom J, Marcello L, Hou L, Wickstead B, Alsmark UC, Arrowsmith C, Atkin RJ, Barron AJ, Bringaud F, Brooks K, Carrington M, Cherevach I, Chillingworth TJ, Churcher C, Clark LN, Corton CH, Cronin A, Davies RM, Doggett J, Djikeng A, Feldblyum T, Field MC, Fraser A, Goodhead I, Hance Z, Harper D, Harris BR, Hauser H, Hostetler J, Ivens A, Jagels K, Johnson D, Johnson J, Jones K, Kerhornou AX, Koo H, Larke N, Landfear S, Larkin C, Leech V, Line A, Lord A, Macleod A, Mooney PJ, Moule S, Martin DM, Morgan GW, Mungall K, Norbertczak H, Ormond D, Pai G, Peacock CS, Peterson J, Quail MA, Rabbinowitsch E, Rajandream MA, Reitter C, Salzberg SL, Sanders M, Schobel S, Sharp S, Simmonds M, Simpson AJ, Tallon L, Turner CM, Tait A, Tivey AR, Van Aken S, Walker D, Wanless D, Wang S, White B, White O, Whitehead S, Woodward J, Wortman J, Adams MD, Embley TM, Gull K, Ullu E, Barry JD, Fairlamb AH, Opperdoes F, Barrell BG, Donelson JE, Hall N, Fraser CM, Melville SE, El-Sayed NM (2005) The genome of the African trypanosome Trypanosoma brucei. Science 309(5733):416–422. doi:10.1126/science.1112642

    CAS  PubMed  Google Scholar 

  65. Ivens AC, Peacock CS, Worthey EA, Murphy L, Aggarwal G, Berriman M, Sisk E, Rajandream MA, Adlem E, Aert R, Anupama A, Apostolou Z, Attipoe P, Bason N, Bauser C, Beck A, Beverley SM, Bianchettin G, Borzym K, Bothe G, Bruschi CV, Collins M, Cadag E, Ciarloni L, Clayton C, Coulson RM, Cronin A, Cruz AK, Davies RM, De Gaudenzi J, Dobson DE, Duesterhoeft A, Fazelina G, Fosker N, Frasch AC, Fraser A, Fuchs M, Gabel C, Goble A, Goffeau A, Harris D, Hertz-Fowler C, Hilbert H, Horn D, Huang Y, Klages S, Knights A, Kube M, Larke N, Litvin L, Lord A, Louie T, Marra M, Masuy D, Matthews K, Michaeli S, Mottram JC, Muller-Auer S, Munden H, Nelson S, Norbertczak H, Oliver K, O’Neil S, Pentony M, Pohl TM, Price C, Purnelle B, Quail MA, Rabbinowitsch E, Reinhardt R, Rieger M, Rinta J, Robben J, Robertson L, Ruiz JC, Rutter S, Saunders D, Schafer M, Schein J, Schwartz DC, Seeger K, Seyler A, Sharp S, Shin H, Sivam D, Squares R, Squares S, Tosato V, Vogt C, Volckaert G, Wambutt R, Warren T, Wedler H, Woodward J, Zhou S, Zimmermann W, Smith DF, Blackwell JM, Stuart KD, Barrell B, Myler PJ (2005) The genome of the kinetoplastid parasite, Leishmania major. Science 309(5733):436–442. doi:10.1126/science.1112680

    PubMed Central  PubMed  Google Scholar 

  66. Izquierdo L, Schulz BL, Rodrigues JA, Guther ML, Procter JB, Barton GJ, Aebi M, Ferguson MA (2009) Distinct donor and acceptor specificities of Trypanosoma brucei oligosaccharyltransferases. EMBO J 28(17):2650–2661. doi:10.1038/emboj.2009.203

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Nasab FP, Schulz BL, Gamarro F, Parodi AJ, Aebi M (2008) All in one: Leishmania major STT3 proteins substitute for the whole oligosaccharyltransferase complex in Saccharomyces cerevisiae. Mol Biol Cell 19(9):3758–3768. doi:10.1091/mbc.E08-05-0467

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Hese K, Otto C, Routier FH, Lehle L (2009) The yeast oligosaccharyltransferase complex can be replaced by STT3 from Leishmania major. Glycobiology 19(2):160–171. doi:10.1093/glycob/cwn118

    CAS  PubMed  Google Scholar 

  69. Bas T, Gao GY, Lvov A, Chandrasekhar KD, Gilmore R, Kobertz WR (2011) Post-translational N-glycosylation of type I transmembrane KCNE1 peptides: implications for membrane protein biogenesis and disease. J Biol Chem 286(32):28150–28159. doi:10.1074/jbc.M111.235168

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Shrimal S, Gilmore R (2013) Glycosylation of closely spaced acceptor sites in human glycoproteins. J Cell Sci 126(Pt 23):5513–5523. doi:10.1242/jcs.139584

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Shrimal S, Trueman SF, Gilmore R (2013) Extreme C-terminal sites are posttranslocationally glycosylated by the STT3B isoform of the OST. J Cell Biol 201(1):81–95. doi:10.1083/jcb.201301031

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Cherepanova NA, Shrimal S, Gilmore R (2014) Oxidoreductase activity is necessary for N-glycosylation of cysteine-proximal acceptor sites in glycoproteins. J Cell Biol 206(4):525–539. doi:10.1083/jcb.201404083

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Spirig U, Bodmer D, Wacker M, Burda P, Aebi M (2005) The 3.4-kDa Ost4 protein is required for the assembly of two distinct oligosaccharyltransferase complexes in yeast. Glycobiology 15(12):1396–1406. doi:10.1093/glycob/cwj025

    CAS  PubMed  Google Scholar 

  74. Schulz BL, Stirnimann CU, Grimshaw JP, Brozzo MS, Fritsch F, Mohorko E, Capitani G, Glockshuber R, Grutter MG, Aebi M (2009) Oxidoreductase activity of oligosaccharyltransferase subunits Ost3p and Ost6p defines site-specific glycosylation efficiency. Proc Natl Acad Sci USA 106(27):11061–11066. doi:10.1073/pnas.0812515106

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Jamaluddin MF, Bailey UM, Tan NY, Stark AP, Schulz BL (2011) Polypeptide binding specificities of Saccharomyces cerevisiae oligosaccharyltransferase accessory proteins Ost3p and Ost6p. Protein Sci 20(5):849–855. doi:10.1002/pro.610

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Mohorko E, Owen RL, Malojcic G, Brozzo MS, Aebi M, Glockshuber R (2014) Structural basis of substrate specificity of human oligosaccharyl transferase subunit N33/Tusc3 and its role in regulating protein N-glycosylation. Structure 22(4):590–601. doi:10.1016/j.str.2014.02.013

    CAS  PubMed  Google Scholar 

  77. Schwarz F, Aebi M (2011) Mechanisms and principles of N-linked protein glycosylation. Curr Opin Struct Biol 21(5):576–582. doi:10.1016/j.sbi.2011.08.005

    CAS  PubMed  Google Scholar 

  78. Szymanski CM, Yao R, Ewing CP, Trust TJ, Guerry P (1999) Evidence for a system of general protein glycosylation in Campylobacter jejuni. Mol Microbiol 32(5):1022–1030

    CAS  PubMed  Google Scholar 

  79. Wacker M, Linton D, Hitchen PG, Nita-Lazar M, Haslam SM, North SJ, Panico M, Morris HR, Dell A, Wren BW, Aebi M (2002) N-linked glycosylation in Campylobacter jejuni and its functional transfer into E. coli. Science 298(5599):1790–1793. doi:10.1126/science.298.5599.1790

    CAS  PubMed  Google Scholar 

  80. Young NM, Brisson JR, Kelly J, Watson DC, Tessier L, Lanthier PH, Jarrell HC, Cadotte N, St Michael F, Aberg E, Szymanski CM (2002) Structure of the N-linked glycan present on multiple glycoproteins in the Gram-negative bacterium, Campylobacter jejuni. J Biol Chem 277(45):42530–42539. doi:10.1074/jbc.M206114200

    CAS  PubMed  Google Scholar 

  81. Glover KJ, Weerapana E, Imperiali B (2005) In vitro assembly of the undecaprenylpyrophosphate-linked heptasaccharide for prokaryotic N-linked glycosylation. Proc Natl Acad Sci USA 102(40):14255–14259. doi:10.1073/pnas.0507311102

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Nothaft H, Liu X, McNally DJ, Li J, Szymanski CM (2009) Study of free oligosaccharides derived from the bacterial N-glycosylation pathway. Proc Natl Acad Sci USA 106(35):15019–15024. doi:10.1073/pnas.0903078106

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Gething MJ, McCammon K, Sambrook J (1986) Expression of wild-type and mutant forms of influenza hemagglutinin: the role of folding in intracellular transport. Cell 46(6):939–950

    CAS  PubMed  Google Scholar 

  84. Hampton RY, Sommer T (2012) Finding the will and the way of ERAD substrate retrotranslocation. Curr Opin Cell Biol 24(4):460–466. doi:10.1016/j.ceb.2012.05.010

    CAS  PubMed  Google Scholar 

  85. Burda P, Aebi M (1999) The dolichol pathway of N-linked glycosylation. Biochim Biophys Acta 1426(2):239–257

    CAS  PubMed  Google Scholar 

  86. Helenius A, Aebi M (2004) Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 73:1019–1049. doi:10.1146/annurev.biochem.73.011303.073752

    CAS  PubMed  Google Scholar 

  87. Sitia R, Braakman I (2003) Quality control in the endoplasmic reticulum protein factory. Nature 426(6968):891–894

    CAS  PubMed  Google Scholar 

  88. Aebi M, Bernasconi R, Clerc S, Molinari M (2010) N-glycan structures: recognition and processing in the ER. Trends Biochem Sci 35(2):74–82. doi:10.1016/j.tibs.2009.10.001

    CAS  PubMed  Google Scholar 

  89. Maattanen P, Gehring K, Bergeron JJ, Thomas DY (2010) Protein quality control in the ER: the recognition of misfolded proteins. Semin Cell Dev Biol 21(5):500–511. doi:10.1016/j.semcdb.2010.03.006

    PubMed  Google Scholar 

  90. Kostova Z, Wolf DH (2003) For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection. EMBO J 22(10):2309–2317

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Xu X, Azakami H, Kato A (2004) P-domain and lectin site are involved in the chaperone function of Saccharomyces cerevisiae calnexin homologue. FEBS Lett 570(1–3):155–160

    CAS  PubMed  Google Scholar 

  92. Totani K, Ihara Y, Matsuo I, Ito Y (2006) Substrate specificity analysis of endoplasmic reticulum glucosidase II using synthetic high mannose-type glycans. J Biol Chem 281(42):31502–31508. doi:10.1074/jbc.M605457200

    CAS  PubMed  Google Scholar 

  93. Caramelo JJ, Parodi AJ (2008) Getting in and out from calnexin/calreticulin cycles. J Biol Chem 283(16):10221–10225. doi:10.1074/jbc.R700048200

    CAS  PubMed Central  PubMed  Google Scholar 

  94. D’Alessio C, Caramelo JJ, Parodi AJ (2010) UDP-GlC:glycoprotein glucosyltransferase-glucosidase II, the ying-yang of the ER quality control. Semin Cell Dev Biol 21(5):491–499. doi:10.1016/j.semcdb.2009.12.014

    PubMed Central  PubMed  Google Scholar 

  95. Moremen KW, Tiemeyer M, Nairn AV (2012) Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol 13(7):448–462. doi:10.1038/nrm3383

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Ninagawa S, Okada T, Sumitomo Y, Kamiya Y, Kato K, Horimoto S, Ishikawa T, Takeda S, Sakuma T, Yamamoto T, Mori K (2014) EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step. J Cell Biol 206(3):347–356. doi:10.1083/jcb.201404075

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Clerc S, Hirsch C, Oggier DM, Deprez P, Jakob C, Sommer T, Aebi M (2009) Htm1 protein generates the N-glycan signal for glycoprotein degradation in the endoplasmic reticulum. J Cell Biol 184(1):159–172. doi:10.1083/jcb.200809198

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Quan EM, Kamiya Y, Kamiya D, Denic V, Weibezahn J, Kato K, Weissman JS (2008) Defining the glycan destruction signal for endoplasmic reticulum-associated degradation. Mol Cell 32(6):870–877. doi:10.1016/j.molcel.2008.11.017

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Hosokawa N, Kamiya Y, Kamiya D, Kato K, Nagata K (2009) Human OS-9, a lectin required for glycoprotein endoplasmic reticulum-associated degradation, recognizes mannose-trimmed N-glycans. J Biol Chem 284(25):17061–17068. doi:10.1074/jbc.M809725200

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Hosokawa N, Wada I, Nagasawa K, Moriyama T, Okawa K, Nagata K (2008) Human XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP. J Biol Chem 283(30):20914–20924. doi:10.1074/jbc.M709336200

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Carvalho P, Goder V, Rapoport TA (2006) Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126(2):361–373. doi:10.1016/j.cell.2006.05.043

    CAS  PubMed  Google Scholar 

  102. Denic V, Quan EM, Weissman JS (2006) A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126(2):349–359. doi:10.1016/j.cell.2006.05.045

    CAS  PubMed  Google Scholar 

  103. Hebert DN, Bernasconi R, Molinari M (2010) ERAD substrates: which way out? Semin Cell Dev Biol 21(5):526–532. doi:10.1016/j.semcdb.2009.12.007

    CAS  PubMed  Google Scholar 

  104. Zhang T, Ye Y (2014) The final moments of misfolded proteins en route to the proteasome. DNA Cell Biol 33(8):477–483. doi:10.1089/dna.2014.2452

    PubMed  Google Scholar 

  105. Suzuki T, Park H, Lennarz WJ (2002) Cytoplasmic peptide:N-glycanase (PNGase) in eukaryotic cells: occurrence, primary structure, and potential functions. FASEB J 16(7):635–641. doi:10.1096/fj.01-0889rev

    CAS  PubMed  Google Scholar 

  106. Hirayama H, Hosomi A, Suzuki T (2014) Physiological and molecular functions of the cytosolic peptide:N-glycanase. Semin Cell Dev Biol. doi:10.1016/j.semcdb.2014.11.009

    PubMed  Google Scholar 

  107. Suzuki T (2015) The cytoplasmic peptide:N-glycanase (Ngly1): basic science encounters a human genetic disorder. J Biochem 157(1):23–34. doi:10.1093/jb/mvu068

    CAS  PubMed  Google Scholar 

  108. Li G, Zhou X, Zhao G, Schindelin H, Lennarz WJ (2005) Multiple modes of interaction of the deglycosylation enzyme, mouse peptide N-glycanase, with the proteasome. Proc Natl Acad Sci USA 102(44):15809–15814. doi:10.1073/pnas.0507155102

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Li G, Zhao G, Zhou X, Schindelin H, Lennarz WJ (2006) The AAA ATPase p97 links peptide N-glycanase to the endoplasmic reticulum-associated E3 ligase autocrine motility factor receptor. Proc Natl Acad Sci USA 103(22):8348–8353. doi:10.1073/pnas.0602747103

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Park H, Suzuki T, Lennarz WJ (2001) Identification of proteins that interact with mammalian peptide:N-glycanase and implicate this hydrolase in the proteasome-dependent pathway for protein degradation. Proc Natl Acad Sci USA 98(20):11163–11168. doi:10.1073/pnas.201393498

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Suzuki T, Park H, Kwofie MA, Lennarz WJ (2001) Rad23 provides a link between the Png1 deglycosylating enzyme and the 26 S proteasome in yeast. J Biol Chem 276(24):21601–21607. doi:10.1074/jbc.M100826200

    CAS  PubMed  Google Scholar 

  112. Kim I, Ahn J, Liu C, Tanabe K, Apodaca J, Suzuki T, Rao H (2006) The Png1-Rad23 complex regulates glycoprotein turnover. J Cell Biol 172(2):211–219. doi:10.1083/jcb.200507149

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Suzuki T (2007) Cytoplasmic peptide:N-glycanase and catabolic pathway for free N-glycans in the cytosol. Semin Cell Dev Biol 18(6):762–769. doi:10.1016/j.semcdb.2007.09.010

    CAS  PubMed  Google Scholar 

  114. Chantret I, Moore SE (2008) Free oligosaccharide regulation during mammalian protein N-glycosylation. Glycobiology 18(3):210–224. doi:10.1093/glycob/cwn003

    CAS  PubMed  Google Scholar 

  115. Anumula KR, Spiro RG (1983) Release of glucose-containing polymannose oligosaccharides during glycoprotein biosynthesis. Studies with thyroid microsomal enzymes and slices. J Biol Chem 258(24):15274–15282

    CAS  PubMed  Google Scholar 

  116. Chavan M, Chen Z, Li G, Schindelin H, Lennarz WJ, Li H (2006) Dimeric organization of the yeast oligosaccharyl transferase complex. Proc Natl Acad Sci USA 103(24):8947–8952. doi:10.1073/pnas.0603262103

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Chantret I, Fasseu M, Zaoui K, Le Bizec C, Yaye HS, Dupre T, Moore SE (2010) Identification of roles for peptide: N-glycanase and endo-β-N-acetylglucosaminidase (Engase1p) during protein N-glycosylation in human HepG2 cells. PLoS ONE 5(7):e11734. doi:10.1371/journal.pone.0011734

    PubMed Central  PubMed  Google Scholar 

  118. Huang C, Harada Y, Hosomi A, Masahara-Negishi Y, Seino J, Fujihira H, Funakoshi Y, Suzuki T, Dohmae N (2015) Endo-β-N-acetylglucosaminidase forms N-GlcNAc protein aggregates during ER-associated degradation in Ngly1-defective cells. Proc Natl Acad Sci USA 112(5):1398–1403. doi:10.1073/pnas.1414593112

    CAS  PubMed  Google Scholar 

  119. Spiro MJ, Spiro RG (1991) Potential regulation of N-glycosylation precursor through oligosaccharide-lipid hydrolase action and glucosyltransferase-glucosidase shuttle. J Biol Chem 266(8):5311–5317

    CAS  PubMed  Google Scholar 

  120. Harada Y, Nakajima K, Masahara-Negishi Y, Freeze HH, Angata T, Taniguchi N, Suzuki T (2013) Metabolically programmed quality control system for dolichol-linked oligosaccharides. Proc Natl Acad Sci USA 110(48):19366–19371. doi:10.1073/pnas.1312187110

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Gao N, Shang J, Lehrman MA (2005) Analysis of glycosylation in CDG-Ia fibroblasts by fluorophore-assisted carbohydrate electrophoresis: implications for extracellular glucose and intracellular mannose 6-phosphate. J Biol Chem 280(18):17901–17909. doi:10.1074/jbc.M500510200

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Villers C, Cacan R, Mir AM, Labiau O, Verbert A (1994) Release of oligomannoside-type glycans as a marker of the degradation of newly synthesized glycoproteins. Biochem J 298(Pt 1):135–142

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Duvet S, Foulquier F, Mir AM, Chirat F, Cacan R (2004) Discrimination between lumenal and cytosolic sites of deglycosylation in endoplasmic reticulum-associated degradation of glycoproteins by using benzyl mannose in CHO cell lines. Glycobiology 14(9):841–849. doi:10.1093/glycob/cwh103

    CAS  PubMed  Google Scholar 

  124. Gao N, Shang J, Huynh D, Manthati VL, Arias C, Harding HP, Kaufman RJ, Mohr I, Ron D, Falck JR, Lehrman MA (2011) Mannose-6-phosphate regulates destruction of lipid-linked oligosaccharides. Mol Biol Cell 22(17):2994–3009. doi:10.1091/mbc.E11-04-0286

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Gao N, Lehrman MA (2013) Mannose-6-phosphate: a regulator of LLO destruction. Methods Mol Biol 1022:277–282. doi:10.1007/978-1-62703-465-4_20

    CAS  PubMed  Google Scholar 

  126. Higashidani A, Bode L, Nishikawa A, Freeze HH (2009) Exogenous mannose does not raise steady state mannose-6-phosphate pools of normal or N-glycosylation-deficient human fibroblasts. Mol Genet Metab 96(4):268–272. doi:10.1016/j.ymgme.2008.12.005

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Moore SE, Bauvy C, Codogno P (1995) Endoplasmic reticulum-to-cytosol transport of free polymannose oligosaccharides in permeabilized HepG2 cells. EMBO J 14(23):6034–6042

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Haga Y, Totani K, Ito Y, Suzuki T (2009) Establishment of a real-time analytical method for free oligosaccharide transport from the ER to the cytosol. Glycobiology 19(9):987–994. doi:10.1093/glycob/cwp075

    CAS  PubMed  Google Scholar 

  129. Moore SE (1998) Transport of free polymannose-type oligosaccharides from the endoplasmic reticulum into the cytosol is inhibited by mannosides and requires a thapsigargin-sensitive calcium store. Glycobiology 8(4):373–381

    CAS  PubMed  Google Scholar 

  130. Moore SE, Spiro RG (1990) Demonstration that Golgi endo-α-d-mannosidase provides a glucosidase-independent pathway for the formation of complex N-linked oligosaccharides of glycoproteins. J Biol Chem 265(22):13104–13112

    CAS  PubMed  Google Scholar 

  131. Spiro MJ, Bhoyroo VD, Spiro RG (1997) Molecular cloning and expression of rat liver endo-α-mannosidase, an N-linked oligosaccharide processing enzyme. J Biol Chem 272(46):29356–29363

    CAS  PubMed  Google Scholar 

  132. Durrant C, Moore SE (2002) Perturbation of free oligosaccharide trafficking in endoplasmic reticulum glucosidase I-deficient and castanospermine-treated cells. Biochem J 365(Pt 1):239–247. doi:10.1042/BJ20011786

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Hirsch C, Blom D, Ploegh HL (2003) A role for N-glycanase in the cytosolic turnover of glycoproteins. EMBO J 22(5):1036–1046. doi:10.1093/emboj/cdg107

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Blom D, Hirsch C, Stern P, Tortorella D, Ploegh HL (2004) A glycosylated type I membrane protein becomes cytosolic when peptide: N-glycanase is compromised. EMBO J 23(3):650–658. doi:10.1038/sj.emboj.7600090

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL (1996) The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84(5):769–779

    CAS  PubMed  Google Scholar 

  136. Wiertz EJ, Tortorella D, Bogyo M, Yu J, Mothes W, Jones TR, Rapoport TA, Ploegh HL (1996) Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384(6608):432–438. doi:10.1038/384432a0

    CAS  PubMed  Google Scholar 

  137. Huppa JB, Ploegh HL (1997) The alpha chain of the T cell antigen receptor is degraded in the cytosol. Immunity 7(1):113–122

    CAS  PubMed  Google Scholar 

  138. Yu H, Kaung G, Kobayashi S, Kopito RR (1997) Cytosolic degradation of T-cell receptor alpha chains by the proteasome. J Biol Chem 272(33):20800–20804

    CAS  PubMed  Google Scholar 

  139. Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, Meisler MH, Goldstein DB (2012) Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet 49(6):353–361. doi:10.1136/jmedgenet-2012-100819

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Freeze HH (2013) Understanding human glycosylation disorders: biochemistry leads the charge. J Biol Chem 288(10):6936–6945. doi:10.1074/jbc.R112.429274

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Enns GM, Shashi V, Bainbridge M, Gambello MJ, Zahir FR, Bast T, Crimian R, Schoch K, Platt J, Cox R, Bernstein JA, Scavina M, Walter RS, Bibb A, Jones M, Hegde M, Graham BH, Need AC, Oviedo A, Schaaf CP, Boyle S, Butte AJ, Chen R, Clark MJ, Haraksingh R, Cowan TM, He P, Langlois S, Zoghbi HY, Snyder M, Gibbs RA, Freeze HH, Goldstein DB (2014) Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med 16(10):751–758. doi:10.1038/gim.2014.22

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Might M, Wilsey M (2014) The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated. Genet Med 16(10):736–737. doi:10.1038/gim.2014.23

    CAS  PubMed  Google Scholar 

  143. Caglayan AO, Comu S, Baranoski JF, Parman Y, Kaymakcalan H, Akgumus GT, Caglar C, Dolen D, Erson-Omay EZ, Harmanci AS, Mishra-Gorur K, Freeze HH, Yasuno K, Bilguvar K, Gunel M (2015) NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy. Eur J Med Genet 58(1):39–43. doi:10.1016/j.ejmg.2014.08.008

    PubMed  Google Scholar 

  144. Haeuw JF, Michalski JC, Strecker G, Spik G, Montreuil J (1991) Cytosolic glycosidases: do they exist? Glycobiology 1(5):487–492

    CAS  PubMed  Google Scholar 

  145. Moore SE, Spiro RG (1994) Intracellular compartmentalization and degradation of free polymannose oligosaccharides released during glycoprotein biosynthesis. J Biol Chem 269(17):12715–12721

    CAS  PubMed  Google Scholar 

  146. Kmiecik D, Herman V, Stroop CJ, Michalski JC, Mir AM, Labiau O, Verbert A, Cacan R (1995) Catabolism of glycan moieties of lipid intermediates leads to a single Man5GlcNAc oligosaccharide isomer: a study with permeabilized CHO cells. Glycobiology 5(5):483–494

    CAS  PubMed  Google Scholar 

  147. Ohashi S, Iwai K, Mega T, Hase S (1999) Quantitation and isomeric structure analysis of free oligosaccharides present in the cytosol fraction of mouse liver: detection of a free disialobiantennary oligosaccharide and glucosylated oligomannosides. J Biochem 126(5):852–858

    CAS  PubMed  Google Scholar 

  148. Iwai K, Mega T, Hase S (1999) Detection of Man5GlcNAc and related free oligomannosides in the cytosol fraction of hen oviduct. J Biochem 125(1):70–74

    CAS  PubMed  Google Scholar 

  149. Suzuki T, Yano K, Sugimoto S, Kitajima K, Lennarz WJ, Inoue S, Inoue Y, Emori Y (2002) Endo-β-N-acetylglucosaminidase, an enzyme involved in processing of free oligosaccharides in the cytosol. Proc Natl Acad Sci USA 99(15):9691–9696. doi:10.1073/pnas.152333599

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Kato T, Fujita K, Takeuchi M, Kobayashi K, Natsuka S, Ikura K, Kumagai H, Yamamoto K (2002) Identification of an endo-β-N-acetylglucosaminidase gene in Caenorhabditis elegans and its expression in Escherichia coli. Glycobiology 12(10):581–587

    CAS  PubMed  Google Scholar 

  151. Kato T, Hatanaka K, Mega T, Hase S (1997) Purification and characterization of endo-β-N-acetylglucosaminidase from hen oviduct. J Biochem 122(6):1167–1173

    CAS  PubMed  Google Scholar 

  152. Shoup VA, Touster O (1976) Purification and characterization of the α-d-mannosidase of rat liver cytosol. J Biol Chem 251(13):3845–3852

    CAS  PubMed  Google Scholar 

  153. Mathur R, Balasubramanian AS (1984) Cobalt-ion chelate affinity chromatography for the purification of brain neutral α-d-mannosidase and its separation from acid α-d-mannosidase. Biochem J 222(1):261–264

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Bischoff J, Kornfeld R (1986) The soluble form of rat liver alpha-mannosidase is immunologically related to the endoplasmic reticulum membrane α-mannosidase. J Biol Chem 261(10):4758–4765

    CAS  PubMed  Google Scholar 

  155. Tulsiani DR, Touster O (1987) Substrate specificities of rat kidney lysosomal and cytosolic α-d-mannosidases and effects of swainsonine suggest a role of the cytosolic enzyme in glycoprotein catabolism. J Biol Chem 262(14):6506–6514

    CAS  PubMed  Google Scholar 

  156. Mathur R, Panneerselvam K, Balasubramanian AS (1988) Co2+-mediated time- and temperature-dependent activation of neutral α-d-mannosidase from monkey brain. Biochem J 253(3):677–685

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Haeuw JF, Strecker G, Wieruszeski JM, Montreuil J, Michalski JC (1991) Substrate specificity of rat liver cytosolic α-d-mannosidase. Novel degradative pathway for oligomannosidic type glycans. Eur J Biochem 202(3):1257–1268

    CAS  PubMed  Google Scholar 

  158. Oku H, Hase S, Ikenaka T (1991) Purification and characterization of neutral alpha-mannosidase that is activated by Co2+ from Japanese quail oviduct. J Biochem 110(1):29–34

    CAS  PubMed  Google Scholar 

  159. Al Daher S, De Gasperi R, Daniel P, Hirani S, Warren C, Winchester B (1992) Substrate specificity of human liver neutral α-mannosidase. Biochem J 286(Pt 1):47–53

    CAS  PubMed Central  PubMed  Google Scholar 

  160. De Gasperi R, Al Daher S, Winchester BG, Warren CD (1992) Substrate specificity of the bovine and feline neutral α-mannosidases. Biochem J 286(Pt 1):55–63

    PubMed Central  PubMed  Google Scholar 

  161. Grard T, Saint-Pol A, Haeuw JF, Alonso C, Wieruszeski JM, Strecker G, Michalski JC (1994) Soluble forms of α-d-mannosidases from rat liver. Separation and characterization of two enzymic forms with different substrate specificities. Eur J Biochem 223(1):99–106

    CAS  PubMed  Google Scholar 

  162. Grard T, Herman V, Saint-Pol A, Kmiecik D, Labiau O, Mir AM, Alonso C, Verbert A, Cacan R, Michalski JC (1996) Oligomannosides or oligosaccharide-lipids as potential substrates for rat liver cytosolic α-d-mannosidase. Biochem J 316(Pt 3):787–792

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Kumano M, Omichi K, Hase S (1996) Substrate specificity of bovine liver cytosolic neutral α-mannosidase activated by Co2+. J Biochem 119(5):991–997

    CAS  PubMed  Google Scholar 

  164. Yamashiro K, Itoh H, Yamagishi M, Natsuka S, Mega T, Hase S (1997) Purification and characterization of neutral α-mannosidase from hen oviduct: studies on the activation mechanism of Co2+. J Biochem 122(6):1174–1181

    CAS  PubMed  Google Scholar 

  165. Yamagishi M, Ishimizu T, Natsuka S, Hase S (2002) Co(II)-regulated substrate specificity of cytosolic alpha-mannosidase. J Biochem 132(2):253–256

    CAS  PubMed  Google Scholar 

  166. Paciotti S, Persichetti E, Klein K, Tasegian A, Duvet S, Hartmann D, Gieselmann V, Beccari T (2014) Accumulation of free oligosaccharides and tissue damage in cytosolic α-mannosidase (Man2c1)-deficient mice. J Biol Chem 289(14):9611–9622. doi:10.1074/jbc.M114.550509

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Oku H, Hase S (1991) Studies on the substrate specificity of neutral alpha-mannosidase purified from Japanese quail oviduct by using sugar chains from glycoproteins. J Biochem 110(6):982–989

    CAS  PubMed  Google Scholar 

  168. Suzuki T, Hara I, Nakano M, Shigeta M, Nakagawa T, Kondo A, Funakoshi Y, Taniguchi N (2006) Man2C1, an α-mannosidase, is involved in the trimming of free oligosaccharides in the cytosol. Biochem J 400(1):33–41. doi:10.1042/BJ20060945

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Wang L, Suzuki T (2013) Dual functions for cytosolic alpha-mannosidase (Man2C1): its down-regulation causes mitochondria-dependent apoptosis independently of its α-mannosidase activity. J Biol Chem 288(17):11887–11896. doi:10.1074/jbc.M112.425702

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Tian Y, Ju JY, Zhou YQ, Liu Y, Zhu LP (2008) Inhibition of alpha-mannosidase Man2c1 gene expression suppresses growth of esophageal carcinoma cells through mitotic arrest and apoptosis. Cancer Sci 99(12):2428–2434. doi:10.1111/j.1349-7006.2008.01019.x

    CAS  PubMed  Google Scholar 

  171. Yue W, Jin YL, Shi GX, Liu Y, Gao Y, Zhao FT, Zhu LP (2004) Suppression of 6A8 α-mannosidase gene expression reduced the potentiality of growth and metastasis of human nasopharyngeal carcinoma. Int J Cancer 108(2):189–195. doi:10.1002/ijc.11536

    CAS  PubMed  Google Scholar 

  172. Xiang ZG, Jiang DD, Liu Y, Zhang LF, Zhu LP (2010) hMan2c1 transgene promotes tumor progress in mice. Transgenic Res 19(1):67–75. doi:10.1007/s11248-009-9299-3

    CAS  PubMed  Google Scholar 

  173. He L, Fan C, Kapoor A, Ingram AJ, Rybak AP, Austin RC, Dickhout J, Cutz JC, Scholey J, Tang D (2011) α-Mannosidase 2C1 attenuates PTEN function in prostate cancer cells. Nat Commun 2:307. doi:10.1038/ncomms1309

    PubMed  Google Scholar 

  174. Kato A, Wang L, Ishii K, Seino J, Asano N, Suzuki T (2011) Calystegine B3 as a specific inhibitor for cytoplasmic α-mannosidase, Man2C1. J Biochem 149(4):415–422. doi:10.1093/jb/mvq153

    CAS  PubMed  Google Scholar 

  175. Butters TD, Alonzi DS, Kukushkin NV, Ren Y, Bleriot Y (2009) Novel mannosidase inhibitors probe glycoprotein degradation pathways in cells. Glycoconj J 26(9):1109–1116. doi:10.1007/s10719-009-9231-3

    CAS  PubMed  Google Scholar 

  176. Bernon C, Carre Y, Kuokkanen E, Slomianny MC, Mir AM, Krzewinski F, Cacan R, Heikinheimo P, Morelle W, Michalski JC, Foulquier F, Duvet S (2011) Overexpression of Man2C1 leads to protein underglycosylation and upregulation of endoplasmic reticulum-associated degradation pathway. Glycobiology 21(3):363–375. doi:10.1093/glycob/cwq169

    CAS  PubMed  Google Scholar 

  177. Weng S, Spiro RG (1996) Endoplasmic reticulum kifunensine-resistant α-mannosidase is enzymatically and immunologically related to the cytosolic α-mannosidase. Arch Biochem Biophys 325(1):113–123. doi:10.1006/abbi.1996.0014

    CAS  PubMed  Google Scholar 

  178. Weng S, Spiro RG (1993) Demonstration that a kifunensine-resistant α-mannosidase with a unique processing action on N-linked oligosaccharides occurs in rat liver endoplasmic reticulum and various cultured cells. J Biol Chem 268(34):25656–25663

    CAS  PubMed  Google Scholar 

  179. Saint-Pol A, Bauvy C, Codogno P, Moore SE (1997) Transfer of free polymannose-type oligosaccharides from the cytosol to lysosomes in cultured human hepatocellular carcinoma HepG2 cells. J Cell Biol 136(1):45–59

    CAS  PubMed Central  PubMed  Google Scholar 

  180. Saint-Pol A, Codogno P, Moore SE (1999) Cytosol-to-lysosome transport of free polymannose-type oligosaccharides. Kinetic and specificity studies using rat liver lysosomes. J Biol Chem 274(19):13547–13555

    CAS  PubMed  Google Scholar 

  181. Strecker G, Herlant-Peers MC, Fournet B, Montreul J (1977) Structure of seven oligosaccharides excreted in the urine of a patient with Sandhoff’s disease (GM2 gangliosidosis-variant O). Eur J Biochem 81(1):165–171

    CAS  PubMed  Google Scholar 

  182. Strecker G, Peers MC, Michalski JC, Hondi-Assah T, Fournet B, Spik G, Montreuil J, Farriaux JP, Maroteaux P, Durand P (1977) Structure of nine sialyl-oligosaccharides accumulated in urine of eleven patients with three different types of sialidosis. Mucolipidosis II and two new types of mucolipidosis. Eur J Biochem 75(2):391–403

    CAS  PubMed  Google Scholar 

  183. Kuriyama M, Ariga T, Ando S, Suzuki M, Yamada T, Miyatake T (1981) Four positional isomers of sialyloligosaccharides isolated from the urine of a patient with sialidosis. J Biol Chem 256(23):12316–12321

    CAS  PubMed  Google Scholar 

  184. Kuriyama M, Ariga T, Ando S, Suzuki M, Yamada T, Miyatake T (1981) Urinary sialyloligosaccharides in adult type sialidosis: occurrence of two positional isomers. Jpn J Exp Med 51(2):129–132

    CAS  PubMed  Google Scholar 

  185. van Pelt J, Hard K, Kamerling JP, Vliegenthart JF, Reuser AJ, Galjaard H (1989) Isolation and structural characterization of twenty-one sialyloligosaccharides from galactosialidosis urine. An intact N,N′-diacetylchitobiose unit at the reducing end of a diantennary structure. Biol Chem Hoppe Seyler 370(3):191–203

    PubMed  Google Scholar 

  186. Michalski JC (1996) Normal and pathological catabolism of glycoproteins. In: Montereuil J, Vliegenthart JFG, Schachter H (eds) Glycoproteins and disease, new comprehensive biochemistry, vol 30. Elsevier, Amsterdam, pp 55–97

    Google Scholar 

  187. Ishizuka A, Hashimto Y, Naka R, Kinoshita M, Kakehi K, Seino J, Funakoshi Y, Suzuki T, Kameyama A, Narimatsu H (2008) Accumulation of free complex-type N-glycans in MKN7 and MKN45 stomach cancer cells. Biochem J 413(2):227–237. doi:10.1042/BJ20071562

    CAS  PubMed  Google Scholar 

  188. Seino J, Wang L, Harada Y, Huang C, Ishii K, Mizushima N, Suzuki T (2013) Basal autophagy is required for the efficient catabolism of sialyloligosaccharides. J Biol Chem 288(37):26898–26907. doi:10.1074/jbc.M113.464503

    CAS  PubMed Central  PubMed  Google Scholar 

  189. Yabu M, Korekane H, Hatano K, Kaneda Y, Nonomura N, Sato C, Kitajima K, Miyamoto Y (2013) Occurrence of free deaminoneuraminic acid (KDN)-containing complex-type N-glycans in human prostate cancers. Glycobiology 23(6):634–642. doi:10.1093/glycob/cws132

    CAS  PubMed  Google Scholar 

  190. Yabu M, Korekane H, Takahashi H, Ohigashi H, Ishikawa O, Miyamoto Y (2013) Accumulation of free Neu5Ac-containing complex-type N-glycans in human pancreatic cancers. Glycoconj J 30(3):247–256. doi:10.1007/s10719-012-9435-9

    CAS  PubMed  Google Scholar 

  191. Huang C, Seino J, Wang L, Haga Y, Suzuki T (2014) Autophagy regulates the stability of sialin, a lysosomal sialic acid transporter. Biosci Biotechnol Biochem. doi:10.1080/09168451.2014.991682

    PubMed Central  Google Scholar 

  192. Iwatsuka K, Watanabe S, Kinoshita M, Kamisue K, Yamada KM, Hayakawa T, Suzuki T, Kakehi K (2014) Free glycans derived from glycoproteins present in human sera. J Chromatogr B Analyt Technol Biomed Life Sci 928:16–21. doi:10.1016/j.jchromb.2013.03.010

    Google Scholar 

  193. Chantret I, Frenoy JP, Moore SE (2003) Free-oligosaccharide control in the yeast Saccharomyces cerevisiae: roles for peptide:N-glycanase (Png1p) and vacuolar mannosidase (Ams1p). Biochem J 373(Pt 3):901–908. doi:10.1042/BJ20030384

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Harada Y, Buser R, Ngwa EM, Hirayama H, Aebi M, Suzuki T (2013) Eukaryotic oligosaccharyltransferase generates free oligosaccharides during N-glycosylation. J Biol Chem 288(45):32673–32684. doi:10.1074/jbc.M113.486985

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Hirayama H, Seino J, Kitajima T, Jigami Y, Suzuki T (2010) Free oligosaccharides to monitor glycoprotein endoplasmic reticulum-associated degradation in Saccharomyces cerevisiae. J Biol Chem 285(16):12390–12404. doi:10.1074/jbc.M109.082081

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Finger A, Knop M, Wolf DH (1993) Analysis of two mutated vacuolar proteins reveals a degradation pathway in the endoplasmic reticulum or a related compartment of yeast. Eur J Biochem 218(2):565–574

    CAS  PubMed  Google Scholar 

  197. Suzuki T, Park H, Hollingsworth NM, Sternglanz R, Lennarz WJ (2000) PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase. J Cell Biol 149(5):1039–1052

    CAS  PubMed Central  PubMed  Google Scholar 

  198. Hosomi A, Tanabe K, Hirayama H, Kim I, Rao H, Suzuki T (2010) Identification of an Htm1 (EDEM)-dependent, Mns1-independent endoplasmic reticulum-associated degradation (ERAD) pathway in Saccharomyces cerevisiae: application of a novel assay for glycoprotein ERAD. J Biol Chem 285(32):24324–24334. doi:10.1074/jbc.M109.095919

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Hosomi A, Suzuki T (2015) Cytoplasmic peptide:N-glycanase cleaves N-glycans on a carboxypeptidase Y mutant during ERAD in Saccharomyces cerevisiae. Biochim Biophys Acta 4:612–619. doi:10.1016/j.bbagen.2014.12.008

    Google Scholar 

  200. Gauss R, Kanehara K, Carvalho P, Ng DT, Aebi M (2011) A complex of Pdi1p and the mannosidase Htm1p initiates clearance of unfolded glycoproteins from the endoplasmic reticulum. Mol Cell 42(6):782–793. doi:10.1016/j.molcel.2011.04.027

    CAS  PubMed  Google Scholar 

  201. Hirayama H, Suzuki T (2011) Metabolism of free oligosaccharides is facilitated in the och1∆ mutant of Saccharomyces cerevisiae. Glycobiology 21(10):1341–1348. doi:10.1093/glycob/cwr073

    CAS  PubMed  Google Scholar 

  202. Kukushkin NV, Alonzi DS, Dwek RA, Butters TD (2011) Demonstration that endoplasmic reticulum-associated degradation of glycoproteins can occur downstream of processing by endomannosidase. Biochem J 438(1):133–142. doi:10.1042/BJ20110186

    CAS  PubMed  Google Scholar 

  203. Alonzi DS, Kukushkin NV, Allman SA, Hakki Z, Williams SJ, Pierce L, Dwek RA, Butters TD (2013) Glycoprotein misfolding in the endoplasmic reticulum: identification of released oligosaccharides reveals a second ER-associated degradation pathway for Golgi-retrieved proteins. Cell Mol Life Sci 70(15):2799–2814. doi:10.1007/s00018-013-1304-6

    CAS  PubMed  Google Scholar 

  204. Karaivanova VK, Spiro RG (2000) Effect of proteasome inhibitors on the release into the cytosol of free polymannose oligosaccharides from glycoproteins. Glycobiology 10(7):727–735

    CAS  PubMed  Google Scholar 

  205. Yoshihisa T, Anraku Y (1989) Nucleotide sequence of AMS1, the structure gene of vacuolar alpha-mannosidase of Saccharomyces cerevisiae. Biochem Biophys Res Commun 163(2):908–915

    CAS  PubMed  Google Scholar 

  206. Chantret I, Kodali VP, Lahmouich C, Harvey DJ, Moore SE (2011) Endoplasmic reticulum-associated degradation (ERAD) and free oligosaccharide generation in Saccharomyces cerevisiae. J Biol Chem 286(48):41786–41800. doi:10.1074/jbc.M111.251371

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Yoshihisa T, Anraku Y (1990) A novel pathway of import of alpha-mannosidase, a marker enzyme of vacuolar membrane, in Saccharomyces cerevisiae. J Biol Chem 265(36):22418–22425

    CAS  PubMed  Google Scholar 

  208. Hutchins MU, Klionsky DJ (2001) Vacuolar localization of oligomeric α-mannosidase requires the cytoplasm to vacuole targeting and autophagy pathway components in Saccharomyces cerevisiae. J Biol Chem 276(23):20491–20498. doi:10.1074/jbc.M101150200

    CAS  PubMed Central  PubMed  Google Scholar 

  209. Scott SV, Guan J, Hutchins MU, Kim J, Klionsky DJ (2001) Cvt19 is a receptor for the cytoplasm-to-vacuole targeting pathway. Mol Cell 7(6):1131–1141

    CAS  PubMed Central  PubMed  Google Scholar 

  210. Shintani T, Huang WP, Stromhaug PE, Klionsky DJ (2002) Mechanism of cargo selection in the cytoplasm to vacuole targeting pathway. Dev Cell 3(6):825–837

    CAS  PubMed Central  PubMed  Google Scholar 

  211. Shintani T, Klionsky DJ (2004) Cargo proteins facilitate the formation of transport vesicles in the cytoplasm to vacuole targeting pathway. J Biol Chem 279(29):29889–29894. doi:10.1074/jbc.M404399200

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Watanabe Y, Noda NN, Kumeta H, Suzuki K, Ohsumi Y, Inagaki F (2010) Selective transport of alpha-mannosidase by autophagic pathways: structural basis for cargo recognition by Atg19 and Atg34. J Biol Chem 285(39):30026–30033. doi:10.1074/jbc.M110.143545

    CAS  PubMed Central  PubMed  Google Scholar 

  213. Suzuki K, Kondo C, Morimoto M, Ohsumi Y (2010) Selective transport of α-mannosidase by autophagic pathways: identification of a novel receptor, Atg34p. J Biol Chem 285(39):30019–30025. doi:10.1074/jbc.M110.143511

    CAS  PubMed Central  PubMed  Google Scholar 

  214. Schwarz M, Knauer R, Lehle L (2005) Yeast oligosaccharyltransferase consists of two functionally distinct sub-complexes, specified by either the Ost3p or Ost6p subunit. FEBS Lett 579(29):6564–6568. doi:10.1016/j.febslet.2005.10.063

    CAS  PubMed  Google Scholar 

  215. Schulz BL, Aebi M (2009) Analysis of glycosylation site occupancy reveals a role for Ost3p and Ost6p in site-specific N-glycosylation efficiency. Mol Cell Proteomics 8(2):357–364. doi:10.1074/mcp.M800219-MCP200

    CAS  PubMed  Google Scholar 

  216. Castro O, Movsichoff F, Parodi AJ (2006) Preferential transfer of the complete glycan is determined by the oligosaccharyltransferase complex and not by the catalytic subunit. Proc Natl Acad Sci USA 103(40):14756–14760. doi:10.1073/pnas.0607086103

    CAS  PubMed Central  PubMed  Google Scholar 

  217. Kelleher DJ, Banerjee S, Cura AJ, Samuelson J, Gilmore R (2007) Dolichol-linked oligosaccharide selection by the oligosaccharyltransferase in protist and fungal organisms. J Cell Biol 177(1):29–37. doi:10.1083/jcb.200611079

    CAS  PubMed Central  PubMed  Google Scholar 

  218. Kitajima T, Chiba Y, Jigami Y (2006) Saccharomyces cerevisiae alpha1,6-mannosyltransferase has a catalytic potential to transfer a second mannose molecule. FEBS J 273(22):5074–5085. doi:10.1111/j.1742-4658.2006.05505.x

    CAS  PubMed  Google Scholar 

  219. Hsu AF, Baynes JW, Heath EC (1974) The role of a dolichol-oligosaccharide as an intermediate in glycoprotein biosynthesis. Proc Natl Acad Sci USA 71(6):2391–2395

    CAS  PubMed Central  PubMed  Google Scholar 

  220. Cacan R, Hoflack B, Verbert A (1980) Fate of oligosaccharide-lipid intermediates synthesized by resting rat-spleen lymphocytes. Eur J Biochem 106(2):473–479

    CAS  PubMed  Google Scholar 

  221. Belard M, Cacan R, Verbert A (1988) Characterization of an oligosaccharide-pyrophosphodolichol pyrophosphatase activity in yeast. Biochem J 255(1):235–242

    CAS  PubMed Central  PubMed  Google Scholar 

  222. Vleugels W, Duvet S, Peanne R, Mir AM, Cacan R, Michalski JC, Matthijs G, Foulquier F (2011) Identification of phosphorylated oligosaccharides in cells of patients with a congenital disorders of glycosylation (CDG-I). Biochimie 93(5):823–833. doi:10.1016/j.biochi.2011.01.016

    CAS  PubMed  Google Scholar 

  223. Peric D, Durrant-Arico C, Delenda C, Dupre T, De Lonlay P, de Baulny HO, Pelatan C, Bader-Meunier B, Danos O, Chantret I, Moore SE (2010) The compartmentalisation of phosphorylated free oligosaccharides in cells from a CDG Ig patient reveals a novel ER-to-cytosol translocation process. PLoS ONE 5(7):e11675. doi:10.1371/journal.pone.0011675

    PubMed Central  PubMed  Google Scholar 

  224. Stark NJ, Heath EC (1979) Glucose-dependent glycosylation of secretory glycoprotein in mouse myeloma cells. Arch Biochem Biophys 192(2):599–609

    CAS  PubMed  Google Scholar 

  225. Gershman H, Robbins PW (1981) Transitory effects of glucose starvation on the synthesis of dolichol-linked oligosaccharides in mammalian cells. J Biol Chem 256(15):7774–7780

    CAS  PubMed  Google Scholar 

  226. Rearick JI, Chapman A, Kornfeld S (1981) Glucose starvation alters lipid-linked oligosaccharide biosynthesis in Chinese hamster ovary cells. J Biol Chem 256(12):6255–6261

    CAS  PubMed  Google Scholar 

  227. Turco SJ, Pickard JL (1982) Altered G-protein glycosylation in vesicular stomatitis virus-infected glucose-deprived baby hamster kidney cells. J Biol Chem 257(15):8674–8679

    CAS  PubMed  Google Scholar 

  228. Baumann H, Jahreis GP (1983) Glucose starvation leads in rat hepatoma cells to partially N-glycosylated glycoproteins including alpha 1-acid glycoproteins. Identification by endoglycolytic digestions in polyacrylamide gels. J Biol Chem 258(6):3942–3949

    CAS  PubMed  Google Scholar 

  229. Doerrler WT, Lehrman MA (1999) Regulation of the dolichol pathway in human fibroblasts by the endoplasmic reticulum unfolded protein response. Proc Natl Acad Sci USA 96(23):13050–13055

    CAS  PubMed Central  PubMed  Google Scholar 

  230. Yanagida K, Natsuka S, Hase S (2006) Structural diversity of cytosolic free oligosaccharides in the human hepatoma cell line, HepG2. Glycobiology 16(4):294–304. doi:10.1093/glycob/cwj074

    CAS  PubMed  Google Scholar 

  231. Suzuki T, Kitajima K, Emori Y, Inoue Y, Inoue S (1997) Site-specific de-N-glycosylation of diglycosylated ovalbumin in hen oviduct by endogenous peptide: N-glycanase as a quality control system for newly synthesized proteins. Proc Natl Acad Sci USA 94(12):6244–6249

    CAS  PubMed Central  PubMed  Google Scholar 

  232. Tarentino AL, Maley F (1976) Purification and properties of an endo-β-N-acetylglucosaminidase from hen oviduct. J Biol Chem 251(21):6537–6543

    CAS  PubMed  Google Scholar 

  233. Seko A, Koketsu M, Nishizono M, Enoki Y, Ibrahim HR, Juneja LR, Kim M, Yamamoto T (1997) Occurence of a sialylglycopeptide and free sialylglycans in hen’s egg yolk. Biochim Biophys Acta 1335(1–2):23–32

    CAS  PubMed  Google Scholar 

  234. Inoue S, Iwasaki M, Ishii K, Kitajima K, Inoue Y (1989) Isolation and structures of glycoprotein-derived free sialooligosaccharides from the unfertilized eggs of Tribolodon hakonensis, a dace. Intracellular accumulation of a novel class of biantennary disialooligosaccharides. J Biol Chem 264(31):18520–18526

    CAS  PubMed  Google Scholar 

  235. Ishii K, Iwasaki M, Inoue S, Kenny PT, Komura H, Inoue Y (1989) Free sialooligosaccharides found in the unfertilized eggs of a freshwater trout, Plecoglossus altivelis. A large storage pool of complex-type bi-, tri-, and tetraantennary sialooligosaccharides. J Biol Chem 264(3):1623–1630

    CAS  PubMed  Google Scholar 

  236. Seko A, Kitajima K, Inoue S, Inoue Y (1991) Identification of free glycan chain liberated by de-N-glycosylation of the cortical alveolar glycopolyprotein (hyosophorin) during early embryogenesis of the Medaka fish, Oryzias latipes. Biochem Biophys Res Commun 180(3):1165–1171

    CAS  PubMed  Google Scholar 

  237. Iwasaki M, Seko A, Kitajima K, Inoue Y, Inoue S (1992) Fish egg glycophosphoproteins have species-specific N-linked glycan units previously found in a storage pool of free glycan chains. J Biol Chem 267(34):24287–24296

    CAS  PubMed  Google Scholar 

  238. Plancke Y, Delplace F, Wieruszeski JM, Maes E, Strecker G (1996) Isolation and structures of glycoprotein-derived free oligosaccharides from the unfertilized eggs of Scyliorhinus caniculus. Characterization of the sequences galactose(α 1–4)galactose(β 1-3)-N-acetylglucosamine and N-acetylneuraminic acid(α 2-6)galactose(β 1-3)-N-acetylglucosamine. Eur J Biochem 235(1–2):199–206

    CAS  PubMed  Google Scholar 

  239. Moriguchi K, Takemoto T, Aoki T, Nakakita S, Natsuka S, Hase S (2007) Free oligosaccharides with Lewis × structure expressed in the segmentation period of zebrafish embryo. J Biochem 142(2):213–227. doi:10.1093/jb/mvm128

    CAS  PubMed  Google Scholar 

  240. Seko A, Kitajima K, Inoue Y, Inoue S (1991) Peptide:N-glycosidase activity found in the early embryos of Oryzias latipes (Medaka fish). The first demonstration of the occurrence of peptide: N-glycosidase in animal cells and its implication for the presence of a de-N-glycosylation system in living organisms. J Biol Chem 266(33):22110–22114

    CAS  PubMed  Google Scholar 

  241. Seko A, Kitajima K, Iwamatsu T, Inoue Y, Inoue S (1999) Identification of two discrete peptide: N-glycanases in Oryzias latipes during embryogenesis. Glycobiology 9(9):887–895

    CAS  PubMed  Google Scholar 

  242. Priem B, Gross KC (1992) Mannosyl-containing and xylosyl-containing glycans promote tomato (Lycopersicon-Esculentum Mill) fruit ripening. Plant Physiol 98(1):399–401. doi:10.1104/Pp.98.1.399

    CAS  PubMed Central  PubMed  Google Scholar 

  243. Yunovitz H, Gross KC (1994) Effect of tunicamycin on metabolism of unconjugated N-glycans in relation to regulation of tomato fruit ripening. Phytochemistry 37(3):663–668. doi:10.1016/S0031-9422(00)90334-0

    CAS  PubMed  Google Scholar 

  244. Yunovitz H, Gross KC (1994) Delay of tomato fruit ripening by an oligosaccharide N-glycan: interactions with Iaa, galactose and lectins. Physiol Plant 90(1):152–156. doi:10.1034/j.1399-3054.1994.900122.x

    CAS  Google Scholar 

  245. Priem B, Morvan H, Gross KC (1994) Unconjugated N-glycans as a new class of plant oligosaccharins. Biochem Soc Trans 22(2):398–402

    CAS  PubMed  Google Scholar 

  246. Berger S, Menudier A, Julien R, Karamanos Y (1995) Endo-N-acetyl-beta-d-glucosaminidase and peptide-N4-(N-acetyl-glucosaminyl) asparagine amidase activities during germination of Raphanus sativus. Phytochemistry 39(3):481–487

    CAS  PubMed  Google Scholar 

  247. Berger S, Menudier A, Julien R, Karamanos Y (1995) Do de-N-glycosylation enzymes have an important role in plant cells? Biochimie 77(9):751–760

    CAS  PubMed  Google Scholar 

  248. Morvan H, Lhernould S (1996) Unconjugated N-glycans probing or signalling in plant tissues. Plant Physiol Biochem 34(3):335–341

    CAS  Google Scholar 

  249. Maeda M, Kimura Y (2014) Structural features of free N-glycans occurring in plants and functional features of de-N-glycosylation enzymes, ENGase, and PNGase: the presence of unusual plant complex type N-glycans. Front Plant Sci 5:429. doi:10.3389/fpls.2014.00429

    PubMed Central  PubMed  Google Scholar 

  250. Priem B, Morvan H, Hafez AMA, Morvan C (1990) Influence of plant glycan of the oligomannoside type on the growth of flax plantlets. Comptes Rendus De L Academie Des Sciences Serie Iii-Sciences De La Vie-Life Sciences 311(11):411–416

    CAS  Google Scholar 

  251. Priem B, Solokwan J, Wieruszeski JM, Strecker G, Nazih H, Morvan H (1990) Isolation and characterization of free glycans of the oligomannoside type from the extracellular medium of a plant-cell suspension. Glycoconj J 7(2):121–132. doi:10.1007/Bf01050375

    CAS  Google Scholar 

  252. Lhernould S, Karamanos Y, Bourgerie S, Strecker G, Julien R, Morvan H (1992) Peptide-N(4)-(N-acetylglucosaminyl)asparagine amidase (Pngase) activity could explain the occurrence of extracellular xylomannosides in a plant-cell suspension. Glycoconj J 9(4):191–197. doi:10.1007/Bf00731164

    CAS  PubMed  Google Scholar 

  253. Priem B, Gitti R, Bush CA, Gross KC (1993) Structure of 10 free N-glycans in ripening tomato fruit: arabinose is a constituent of a plant N-glycan. Plant Physiol 102(2):445–458. doi:10.1104/Pp.102.2.445

    CAS  PubMed Central  PubMed  Google Scholar 

  254. Lhernould S, Karamanos Y, Priem B, Morvan H (1994) Carbon starvation increases endoglycosidase activities and production of unconjugated N-glycans in silene alba cell-suspension cultures. Plant Physiol 106(2):779–784. doi:10.1104/Pp.106.2.779

    CAS  PubMed Central  PubMed  Google Scholar 

  255. Yunovitz H, Livsey JN, Gross KC (1996) Unconjugated Man(5)GlcNac occurs in vegetative tissues of tomato. Phytochemistry 42(3):607–610. doi:10.1016/0031-9422(95)00956-6

    CAS  PubMed  Google Scholar 

  256. Faugeron C, Lhernould S, Lemoine J, Costa G, Morvan H (1997) Identification of unconjugated N-glycans in strawberry plants. Plant Physiol Biochem 35(11):891–895

    CAS  Google Scholar 

  257. Faugeron C, Lhernould S, Maes E, Lerouge P, Strecker G, Morvan H (1997) Tomato plant leaves also contain unconjugated N-glycans. Plant Physiol Biochem 35(1):73–79

    CAS  Google Scholar 

  258. Kimura Y, Takagi S, Shiraishi T (1997) Occurrence of free N-glycans in pea (Pisum sativum L.) seedlings. Biosci Biotechnol Biochem 61(5):924–926

    CAS  Google Scholar 

  259. Kimura Y, Kitahara E (2000) Structural analysis of free N-glycans occurring in soybean seedlings and dry seeds. Biosci Biotechnol Biochem 64(9):1847–1855. doi:10.1271/Bbb.64.1847

    CAS  PubMed  Google Scholar 

  260. Kimura Y, Matsuo S (2000) Free N-glycans already occur at an early stage of seed development. J Biochem 127(6):1013–1019

    CAS  PubMed  Google Scholar 

  261. Kimura Y, Matsuo S, Tsurusaki S, Kimura M, Hara-Nishimura I, Nishimura M (2002) Subcellular localization of endo-β-N-acetylglucosaminidase and high-mannose type free N-glycans in plant cell. Biochim Biophys Acta 1570(1):38–46

    CAS  PubMed  Google Scholar 

  262. Nakamura K, Inoue M, Yoshiie T, Hosoi K, Kimura Y (2008) Changes in structural features of free N-glycan and endoglycosidase activity during tomato fruit ripening. Biosci Biotechnol Biochem 72(11):2936–2945. doi:10.1271/bbb.80414

    CAS  PubMed  Google Scholar 

  263. Maeda M, Kimura M, Kimura Y (2010) Intracellular and extracellular free N-glycans produced by plant cells: occurrence of unusual plant complex-type free N-glycans in extracellular spaces. J Biochem 148(6):681–692. doi:10.1093/jb/mvq102

    CAS  PubMed  Google Scholar 

  264. Kimura Y, Takeoka Y, Inoue M, Maeda M, Fujiyama K (2011) Double-knockout of putative endo-β-N-acetylglucosaminidase (ENGase) genes in Arabidopsis thaliana: loss of ENGase activity induced accumulation of high-mannose type free N-glycans bearing N, N′-acetylchitobiosyl unit. Biosci Biotechnol Biochem 75(5):1019–1021

    CAS  PubMed  Google Scholar 

  265. Takahashi N (1977) Demonstration of a new amidase acting on glycopeptides. Biochem Biophys Res Commun 76(4):1194–1201. doi:10.1016/0006-291x(77)90982-2

    CAS  PubMed  Google Scholar 

  266. Takahashi N, Nishibe H (1978) Some characteristics of a new glycopeptidase acting on aspartylglycosylamine linkages. J Biochem 84(6):1467–1473

    CAS  PubMed  Google Scholar 

  267. Sugiyama K, Ishihara H, Tejima S, Takahashi N (1983) Demonstration of a new glycopeptidase, from Jack-Bean meal, acting on aspartylglucosylamine linkages. Biochem Biophys Res Commun 112(1):155–160. doi:10.1016/0006-291x(83)91810-7

    CAS  PubMed  Google Scholar 

  268. Taga EM, Waheed A, Van Etten RL (1984) Structural and chemical characterization of a homogeneous peptide N-glycosidase from almond. Biochemistry 23(5):815–822

    CAS  PubMed  Google Scholar 

  269. Plummer TH Jr, Phelan AW, Tarentino AL (1987) Detection and quantification of peptide-N4-(N-acetyl-β-glucosaminyl)asparagine amidases. Eur J Biochem 163(1):167–173

    CAS  PubMed  Google Scholar 

  270. Yet MG, Wold F (1988) Purification and characterization of two glycopeptide hydrolases from jack beans. J Biol Chem 263(1):118–122

    CAS  PubMed  Google Scholar 

  271. Lhernould S, Karamanos Y, Lerouge P, Morvan H (1995) Characterization of the peptide-N-4-(N-Acetylglucosaminyl) asparagine amidase (Pngase Se) from silene alba cells. Glycoconj J 12(1):94–98. doi:10.1007/Bf00731874

    CAS  PubMed  Google Scholar 

  272. Berger S, Menudier A, Julien R, Karamanos Y (1996) Regulation of de-N-glycosylation enzymes in germinating radish seeds. Plant Physiol 112(1):259–264

    CAS  PubMed Central  PubMed  Google Scholar 

  273. Altmann F, Paschinger K, Dalik T, Vorauer K (1998) Characterisation of peptide-N4-(N-acetyl-β-glucosaminyl)asparagine amidase A and its N-glycans. Eur J Biochem 252(1):118–123

    CAS  PubMed  Google Scholar 

  274. Kimura Y, Ohno A (1998) A new peptide-N-4-(acetyl-β-glucosaminyl)asparagine amidase from soybean (Glycine max) seeds: purification and substrate specificity. Biosci Biotechnol Biochem 62(2):412–418. doi:10.1271/Bbb.62.412

    CAS  PubMed  Google Scholar 

  275. Chang T, Kuo MC, Khoo KH, Inoue S, Inoue Y (2000) Developmentally regulated expression of a peptide:N-glycanase during germination of rice seeds (Oryza sativa) and its purification and characterization. J Biol Chem 275(1):129–134

    CAS  PubMed  Google Scholar 

  276. Vuylsteker C, Cuvellier G, Berger S, Faugeron C, Karamanos Y (2000) Evidence of two enzymes performing the de-N-glycosylation of proteins in barley: expression during germination, localization within the grain and set-up during grain formation. J Exp Bot 51(346):839–845

    CAS  PubMed  Google Scholar 

  277. Hossain MA, Nakano R, Nakamura K, Kimura Y (2010) Molecular identification and characterization of an acidic peptide:N-glycanase from tomato (Lycopersicum esculentum) fruits. J Biochem 147(2):157–165. doi:10.1093/jb/mvp157

    CAS  PubMed  Google Scholar 

  278. Chien S, Weinburg R, Li S, Li Y (1976) Endo-β-N-acetylglucosaminidase from fig latex. Biochem Biophys Res Commun 76(2):317–323

    CAS  PubMed  Google Scholar 

  279. Ogata-Arakawa M, Muramatsu T, Kobata A (1977) Partial purification and characterization of an endo-β-N-acetylglucosaminidase from fig extract. J Biochem 82(2):611–614

    CAS  PubMed  Google Scholar 

  280. Li SC, Asakawa M, Hirabayashi Y, Li Y (1981) Isolation of two endo-β-N-acetylglucosaminidases from fig latex. Biochim Biophys Acta 660(2):278–283

    CAS  PubMed  Google Scholar 

  281. Nishiyama A, Nishimoto T, Yamaguchi H (1991) A novel endo-β-N-acetyl-glucosaminidase from shoots of phyllostachys-heterocycla var pubescens. Agric Biol Chem 55(4):1155–1158

    CAS  Google Scholar 

  282. Kimura Y, Iwata K, Sumi Y, Takagi S (1996) Purification and substrate specificity of an endo-β-N-acetylglucosaminidase from pea (Pisum sativum) seeds. Biosci Biotechnol Biochem 60(2):228–232

    CAS  PubMed  Google Scholar 

  283. Kimura Y, Matsuo S, Takagi S (1998) Enzymatic properties of a Ginkgo biloba endo-β-N-acetylglucosaminidase and N-glycan structures of storage glycoproteins in the seeds. Biosci Biotechnol Biochem 62(2):253–261. doi:10.1271/Bbb.62.253

    CAS  PubMed  Google Scholar 

  284. Kimura Y, Tokuda T, Ohno A, Tanaka H, Ishiguro Y (1998) Enzymatic properties of endo-β-N-acetylglucosaminidases from developing tomato fruits and soybean seeds: substrate specificity of plant origin endoglycosidase. Biochim Biophys Acta 1381(1):27–36

    CAS  PubMed  Google Scholar 

  285. Nakamura K, Inoue M, Maeda M, Nakano R, Hosoi K, Fujiyama K, Kimura Y (2009) Molecular cloning and gene expression analysis of tomato endo-β-N-acetylglucosaminidase, an endoglycosidase involved in the production of high-mannose type free N-glycans during tomato fruit ripening. Biosci Biotechnol Biochem 73(2):461–464. doi:10.1271/bbb.80889

    CAS  PubMed  Google Scholar 

  286. Fischl RM, Stadlmann J, Grass J, Altmann F, Leonard R (2011) The two endo-β-N-acetylglucosaminidase genes from Arabidopsis thaliana encode cytoplasmic enzymes controlling free N-glycan levels. Plant Mol Biol 77(3):275–284. doi:10.1007/s11103-011-9808-7

    CAS  PubMed  Google Scholar 

  287. Kim YC, Jahren N, Stone MD, Udeshi ND, Markowski TW, Witthuhn BA, Shabanowitz J, Hunt DF, Olszewski NE (2013) Identification and origin of N-linked beta-d-N-acetylglucosamine monosaccharide modifications on Arabidopsis proteins. Plant Physiol 161(1):455–464. doi:10.1104/pp.112.208900

    CAS  PubMed Central  PubMed  Google Scholar 

  288. Diepold A, Li G, Lennarz WJ, Nurnberger T, Brunner F (2007) The Arabidopsis AtPNG1 gene encodes a peptide: N-glycanase. Plant J 52(1):94–104. doi:10.1111/j.1365-313X.2007.03215.x

    CAS  PubMed  Google Scholar 

  289. Masahara-Negishi Y, Hosomi A, Della Mea M, Serafini-Fracassini D, Suzuki T (2012) A plant peptide: N-glycanase orthologue facilitates glycoprotein ER-associated degradation in yeast. Biochim Biophys Acta 1820(10):1457–1462. doi:10.1016/j.bbagen.2012.05.009

    CAS  PubMed  Google Scholar 

  290. Funakoshi Y, Negishi Y, Gergen JP, Seino J, Ishii K, Lennarz WJ, Matsuo I, Ito Y, Taniguchi N, Suzuki T (2010) Evidence for an essential deglycosylation-independent activity of PNGase in Drosophila melanogaster. PLoS ONE 5(5):e10545. doi:10.1371/journal.pone.0010545

    PubMed Central  PubMed  Google Scholar 

  291. Kato T, Kitamura K, Maeda M, Kimura Y, Katayama T, Ashida H, Yamamoto K (2007) Free oligosaccharides in the cytosol of Caenorhabditis elegans are generated through endoplasmic reticulum-golgi trafficking. J Biol Chem 282(30):22080–22088. doi:10.1074/jbc.M700805200

    CAS  PubMed  Google Scholar 

  292. Katoh T, Ashida H, Yamamoto K (2009) Generation and metabolism of cytosolic free oligosaccharides in Caenorhabditis elegans. Trends Glycosci Glycotechnol 21(119):163–177. doi:10.4052/Tigg.21.163

    CAS  Google Scholar 

  293. Kato T, Kawahara A, Ashida H, Yamamoto K (2007) Unique peptide:N-glycanase of Caenorhabditis elegans has activity of protein disulphide reductase as well as of deglycosylation. J Biochem 142(2):175–181. doi:10.1093/jb/mvm117

    CAS  PubMed  Google Scholar 

  294. Suzuki T, Tanabe K, Hara I, Taniguchi N, Colavita A (2007) Dual enzymatic properties of the cytoplasmic peptide: N-glycanase in C. elegans. Biochem Biophys Res Commun 358(3):837–841. doi:10.1016/j.bbrc.2007.04.199

    CAS  PubMed  Google Scholar 

  295. Habibi-Babadi N, Su A, de Carvalho CE, Colavita A (2010) The N-glycanase png-1 acts to limit axon branching during organ formation in Caenorhabditis elegans. J Neurosci 30(5):1766–1776. doi:10.1523/JNEUROSCI.4962-08.2010

    CAS  PubMed  Google Scholar 

  296. Dwivedi R, Nothaft H, Reiz B, Whittal RM, Szymanski CM (2013) Generation of free oligosaccharides from bacterial protein N-linked glycosylation systems. Biopolymers 99(10):772–783. doi:10.1002/bip.22296

    CAS  PubMed  Google Scholar 

  297. Liu X, McNally DJ, Nothaft H, Szymanski CM, Brisson JR, Li J (2006) Mass spectrometry-based glycomics strategy for exploring N-linked glycosylation in eukaryotes and bacteria. Anal Chem 78(17):6081–6087. doi:10.1021/ac060516m

    CAS  PubMed  Google Scholar 

  298. Nothaft H, Scott NE, Vinogradov E, Liu X, Hu R, Beadle B, Fodor C, Miller WG, Li J, Cordwell SJ, Szymanski CM (2012) Diversity in the protein N-glycosylation pathways within the Campylobacter genus. Mol Cell Proteomics 11(11):1203–1219. doi:10.1074/mcp.M112.021519

    PubMed Central  PubMed  Google Scholar 

  299. Nothaft H, Liu X, Li J, Szymanski CM (2010) Campylobacter jejuni free oligosaccharides: function and fate. Virulence 1(6):546–550

    PubMed  Google Scholar 

  300. Denzel MS, Storm NJ, Gutschmidt A, Baddi R, Hinze Y, Jarosch E, Sommer T, Hoppe T, Antebi A (2014) Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 156(6):1167–1178. doi:10.1016/j.cell.2014.01.061

    CAS  PubMed  Google Scholar 

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Acknowledgments

We are grateful to the members of Glycometabolome Team for sharing their passion for science as well as fruitful discussions. TS would like to thank Drs. Christine Szymanski and Harald Nothaft (University of Alberta, Canada) for their invaluable input on FNG generation in bacteria. Research regarding the generation and degradation of FNG by the Glycometabolome Team have been supported by the following research grants: Mizutani Foundation for Glycoscience, CREST (Japan Science and Technology Agency), Kakiuchi Memorial Research Grant (The Japanese Biochemical Society) (to T. S.); Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (24770134 and 26650040 to Y. H.; 22570148, 25291030 and 26110725 to T. S.); Incentive Research Projects (RIKEN) to Y. H. and H. H.

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  1. Glycometabolome Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan

    Yoichiro Harada, Hiroto Hirayama & Tadashi Suzuki

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  1. Yoichiro Harada
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  2. Hiroto Hirayama
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Correspondence to Tadashi Suzuki.

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Harada, Y., Hirayama, H. & Suzuki, T. Generation and degradation of free asparagine-linked glycans. Cell. Mol. Life Sci. 72, 2509–2533 (2015). https://doi.org/10.1007/s00018-015-1881-7

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