Skip to main content

Advertisement

SpringerLink
Log in

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

In healthy cell, inappropriate accumulation of poor or damaged proteins is prevented by cellular quality control system. Autophagy and ubiquitin proteasome system (UPS) provides regular cytoprotection against proteotoxicity induced by abnormal or disruptive proteins. E3 ubiquitin ligases are crucial components in this defense mechanism. Mahogunin Ring Finger-1 (MGRN1), an E3 ubiquitin ligase of the Really Interesting New Gene (RING) finger family, plays a pivotal role in many biological and cellular mechanisms. Previous findings indicate that lack of functions of MGRN1 can cause spongiform neurodegeneration, congenital heart defects, abnormal left-right patterning, and mitochondrial dysfunctions in mice brains. However, the detailed molecular pathomechanism of MGRN1 in cellular functions and diseases is not well known. This article comprehensively represents the molecular nature, characterization, and functions of MGRN1; we also summarize possible beneficiary aspects of this novel E3 ubiquitin ligase. Here, we review recent literature on the role of MGRN1 in the neuro-pathobiological mechanisms, with precise focus on the processes of neurodegeneration, and thereby propose new lines of potential targets for therapeutic intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Dobson CM (2003) Protein folding and misfolding. Nature 426(6968):884–890. doi:10.1038/nature02261

    Article  CAS  PubMed  Google Scholar 

  2. Duncan R, Hershey JW (1983) Identification and quantitation of levels of protein synthesis initiation factors in crude HeLa cell lysates by two-dimensional polyacrylamide gel electrophoresis. J Biol Chem 258(11):7228–7235

    CAS  PubMed  Google Scholar 

  3. Ingolia NT, Lareau LF, Weissman JS (2011) Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147(4):789–802. doi:10.1016/j.cell.2011.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G et al (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416(6880):507–511. doi:10.1038/416507a

    Article  CAS  PubMed  Google Scholar 

  5. Chen B, Retzlaff M, Roos T, Frydman J (2011) Cellular strategies of protein quality control. Cold Spring Harb Perspect Biol 3(8):a004374. doi:10.1101/cshperspect.a004374

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU (2013) Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem 82:323–355. doi:10.1146/annurev-biochem-060208-092442

    Article  CAS  PubMed  Google Scholar 

  7. Fimia GM, Kroemer G, Piacentini M (2013) Molecular mechanisms of selective autophagy. Cell Death Differ 20(1):1–2. doi:10.1038/cdd.2012.97

    Article  CAS  PubMed  Google Scholar 

  8. Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Furst DO, Saftig P et al (2010) Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol 20(2):143–148. doi:10.1016/j.cub.2009.11.022

    Article  CAS  PubMed  Google Scholar 

  9. Ulbricht A, Eppler FJ, Tapia VE, van der Ven PF, Hampe N, Hersch N, Vakeel P, Stadel D et al (2013) Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy. Curr Biol 23(5):430–435. doi:10.1016/j.cub.2013.01.064

    Article  CAS  PubMed  Google Scholar 

  10. Kaushik S, Cuervo AM (2012) Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 22(8):407–417. doi:10.1016/j.tcb.2012.05.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kettern N, Dreiseidler M, Tawo R, Hohfeld J (2010) Chaperone-assisted degradation: multiple paths to destruction. Biol Chem 391(5):481–489. doi:10.1515/BC.2010.058

    Article  CAS  PubMed  Google Scholar 

  12. Green M (1989) Genetic variants and strains of the laboratory mouse., vol 12–403. Catalog of mutant genes and polymorphic loci. Oxford University Press, New York

    Google Scholar 

  13. Lane PW, Green MC (1960) Mahogany, a recessive color mutation in linkage group v of the mouse. J Hered 51(5):228–230

    Google Scholar 

  14. Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1998) Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res 5(1):31–39

    Article  CAS  PubMed  Google Scholar 

  15. Phan LK, Lin F, LeDuc CA, Chung WK, Leibel RL (2002) The mouse mahoganoid coat color mutation disrupts a novel C3HC4 RING domain protein. J Clin Invest 110(10):1449–1459. doi:10.1172/JCI16131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. He L, Lu XY, Jolly AF, Eldridge AG, Watson SJ, Jackson PK, Barsh GS, Gunn TM (2003) Spongiform degeneration in mahoganoid mutant mice. Science 299(5607):710–712. doi:10.1126/science.1079694

    Article  CAS  PubMed  Google Scholar 

  17. He L, Eldridge AG, Jackson PK, Gunn TM, Barsh GS (2003) Accessory proteins for melanocortin signaling: attractin and mahogunin. Ann N Y Acad Sci 994:288–298

    Article  CAS  PubMed  Google Scholar 

  18. Bagher P, Jiao J, Owen Smith C, Cota CD, Gunn TM (2006) Characterization of mahogunin ring finger-1 expression in mice. Pigment Cell Res 19(6):635–643. doi:10.1111/j.1600-0749.2006.00340.x

    Article  CAS  PubMed  Google Scholar 

  19. Perez-Oliva AB, Olivares C, Jimenez-Cervantes C, Garcia-Borron JC (2009) Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits signaling from melanocortin receptor by competition with Galphas. J Biol Chem 284(46):31714–31725. doi:10.1074/jbc.M109.028100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chhangani D, Jana NR, Mishra A (2013) Misfolded proteins recognition strategies of E3 ubiquitin ligases and neurodegenerative diseases. Mol Neurobiol 47(1):302–312. doi:10.1007/s12035-012-8351-0

    Article  CAS  PubMed  Google Scholar 

  21. Matz A, Lee SJ, Schwedhelm-Domeyer N, Zanini D, Holubowska A, Kannan M, Farnworth M, Jahn O et al (2015) Regulation of neuronal survival and morphology by the E3 ubiquitin ligase RNF157. Cell Death Differ 22(4):626–642. doi:10.1038/cdd.2014.163

    Article  CAS  PubMed  Google Scholar 

  22. Kim JH, Kim WT (2013) The Arabidopsis RING E3 ubiquitin ligase AtAIRP3/LOG2 participates in positive regulation of high-salt and drought stress responses. Plant Physiol 162(3):1733–1749. doi:10.1104/pp.113.220103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Guerra DD, Pratelli R, Kraft E, Callis J, Pilot G (2013) Functional conservation between mammalian MGRN1 and plant LOG2 ubiquitin ligases. FEBS Lett 587(21):3400–3405. doi:10.1016/j.febslet.2013.08.045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jiao J, Sun K, Walker WP, Bagher P, Cota CD, Gunn TM (2009) Abnormal regulation of TSG101 in mice with spongiform neurodegeneration. Biochim Biophys Acta 1792(10):1027–1035. doi:10.1016/j.bbadis.2009.08.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Borden KL (2000) RING domains: master builders of molecular scaffolds? J Mol Biol 295(5):1103–1112. doi:10.1006/jmbi.1999.3429

    Article  CAS  PubMed  Google Scholar 

  26. Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM (1999) RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A 96(20):11364–11369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Borden KL, Freemont PS (1996) The RING finger domain: a recent example of a sequence-structure family. Curr Opin Struct Biol 6(3):395–401

    Article  CAS  PubMed  Google Scholar 

  28. Kim MS, Pinto SM, Getnet D, Nirujogi RS, Manda SS, Chaerkady R, Madugundu AK, Kelkar DS et al (2014) A draft map of the human proteome. Nature 509(7502):575–581. doi:10.1038/nature13302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Olzscha H, Schermann SM, Woerner AC, Pinkert S, Hecht MH, Tartaglia GG, Vendruscolo M, Hayer-Hartl M et al (2011) Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144(1):67–78. doi:10.1016/j.cell.2010.11.050

    Article  CAS  PubMed  Google Scholar 

  30. Dobson CM (2004) Principles of protein folding, misfolding and aggregation. Semin Cell Dev Biol 15(1):3–16. doi:10.1016/j.semcdb.2003.12.008

    Article  CAS  PubMed  Google Scholar 

  31. Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6(1):11–22. doi:10.1038/nrn1587

    Article  CAS  PubMed  Google Scholar 

  32. Walker LC, Diamond MI, Duff KE, Hyman BT (2013) Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol 70(3):304–310. doi:10.1001/jamaneurol.2013.1453

    Article  PubMed  Google Scholar 

  33. Demand J, Alberti S, Patterson C, Hohfeld J (2001) Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr Biol 11(20):1569–1577

    Article  CAS  PubMed  Google Scholar 

  34. Chhangani D, Nukina N, Kurosawa M, Amanullah A, Joshi V, Upadhyay A, Mishra A (2014) Mahogunin ring finger 1 suppresses misfolded polyglutamine aggregation and cytotoxicity. Biochim Biophys Acta. doi:10.1016/j.bbadis.2014.04.014

    PubMed  Google Scholar 

  35. Jacomy H, Talbot PJ (2003) Vacuolating encephalitis in mice infected by human coronavirus OC43. Virology 315(1):20–33

    Article  CAS  PubMed  Google Scholar 

  36. Fraser JR (2002) What is the basis of transmissible spongiform encephalopathy induced neurodegeneration and can it be repaired? Neuropathol Appl Neurobiol 28(1):1–11

    Article  CAS  PubMed  Google Scholar 

  37. Kim BY, Olzmann JA, Barsh GS, Chin LS, Li L (2007) Spongiform neurodegeneration-associated E3 ligase Mahogunin ubiquitylates TSG101 and regulates endosomal trafficking. Mol Biol Cell 18(4):1129–1142. doi:10.1091/mbc.E06-09-0787

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Amit I, Yakir L, Katz M, Zwang Y, Marmor MD, Citri A, Shtiegman K, Alroy I et al (2004) Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding. Genes Dev 18(14):1737–1752. doi:10.1101/gad.294904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li L, Liao J, Ruland J, Mak TW, Cohen SN (2001) A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control. Proc Natl Acad Sci U S A 98(4):1619–1624. doi:10.1073/pnas.98.4.1619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cheng TH, Cohen SN (2007) Human MDM2 isoforms translated differentially on constitutive versus p53-regulated transcripts have distinct functions in the p53/MDM2 and TSG101/MDM2 feedback control loops. Mol Cell Biol 27(1):111–119. doi:10.1128/MCB.00235-06

    Article  CAS  PubMed  Google Scholar 

  41. Sun K, Johnson BS, Gunn TM (2007) Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrn1) mutant mice. Neurobiol Aging 28(12):1840–1852. doi:10.1016/j.neurobiolaging.2007.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Miller KA, Gunn TM, Carrasquillo MM, Lamoreux ML, Galbraith DB, Barsh GS (1997) Genetic studies of the mouse mutations mahogany and mahoganoid. Genetics 146(4):1407–1415

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Prusiner SB (1991) Molecular biology of prion diseases. Science 252(5012):1515–1522

    Article  CAS  PubMed  Google Scholar 

  44. Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z et al (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A 90(23):10962–10966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Miesbauer M, Rambold AS, Winklhofer KF, Tatzelt J (2010) Targeting of the prion protein to the cytosol: mechanisms and consequences. Curr Issues Mol Biol 12(2):109–118

    CAS  PubMed  Google Scholar 

  46. Chakrabarti O, Hegde RS (2009) Functional depletion of mahogunin by cytosolically exposed prion protein contributes to neurodegeneration. Cell 137(6):1136–1147. doi:10.1016/j.cell.2009.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Silvius D, Pitstick R, Ahn M, Meishery D, Oehler A, Barsh GS, DeArmond SJ, Carlson GA et al (2013) Levels of the Mahogunin Ring Finger 1 E3 ubiquitin ligase do not influence prion disease. PLoS One 8(1), e55575. doi:10.1371/journal.pone.0055575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Uchiyama K, Muramatsu N, Yano M, Usui T, Miyata H, Sakaguchi S (2013) Prions disturb post-Golgi trafficking of membrane proteins. Nat Commun 4:1846. doi:10.1038/ncomms2873

    Article  PubMed  CAS  Google Scholar 

  49. Yuan F, Yang L, Zhang Z, Wu W, Zhou X, Yin X, Zhao D (2013) Cellular prion protein (PrPC) of the neuron cell transformed to a PK-resistant protein under oxidative stress, comprising main mitochondrial damage in prion diseases. J Mol Neurosci : MN 51(1):219–224. doi:10.1007/s12031-013-0008-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Winkler J, Tyedmers J, Bukau B, Mogk A (2012) Hsp70 targets Hsp100 chaperones to substrates for protein disaggregation and prion fragmentation. J Cell Biol 198(3):387–404. doi:10.1083/jcb.201201074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lin Z, Zhao D, Yang L (2013) Interaction between misfolded PrP and the ubiquitin-proteasome system in prion-mediated neurodegeneration. Acta Biochim Biophys Sin (Shanghai) 45(6):477–484. doi:10.1093/abbs/gmt020

    Article  CAS  Google Scholar 

  52. Liberski PP, Brown DR, Sikorska B, Caughey B, Brown P (2008) Cell death and autophagy in prion diseases (transmissible spongiform encephalopathies). Folia Neuropathol 46(1):1–25

    CAS  PubMed  Google Scholar 

  53. Du Toit A (2014) Post-translational modification: sweetening protein quality control. Nat Rev Mol Cell Biol 15(5):295. doi:10.1038/nrm3787

    Article  PubMed  CAS  Google Scholar 

  54. van Oosten-Hawle P, Morimoto RI (2014) Transcellular chaperone signaling: an organismal strategy for integrated cell stress responses. J Exp Biol 217(Pt 1):129–136. doi:10.1242/jeb.091249

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Scotter EL, Vance C, Nishimura AL, Lee YB, Chen HJ, Urwin H, Sardone V, Mitchell JC et al (2014) Differential roles of the ubiquitin proteasome system and autophagy in the clearance of soluble and aggregated TDP-43 species. J Cell Sci 127(Pt 6):1263–1278. doi:10.1242/jcs.140087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sontag EM, Vonk WI, Frydman J (2014) Sorting out the trash: the spatial nature of eukaryotic protein quality control. Curr Opin Cell Biol 26:139–146. doi:10.1016/j.ceb.2013.12.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wolff S, Weissman JS, Dillin A (2014) Differential scales of protein quality control. Cell 157(1):52–64. doi:10.1016/j.cell.2014.03.007

    Article  CAS  PubMed  Google Scholar 

  58. Polling S, Mok YF, Ramdzan YM, Turner BJ, Yerbury JJ, Hill AF, Hatters DM (2014) Misfolded polyglutamine, polyalanine, and superoxide dismutase 1 aggregate via distinct pathways in the cell. J Biol Chem 289(10):6669–6680. doi:10.1074/jbc.M113.520189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mosser DD, Caron AW, Bourget L, Denis-Larose C, Massie B (1997) Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol Cell Biol 17(9):5317–5327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kakkar V, Meister-Broekema M, Minoia M, Carra S, Kampinga HH (2014) Barcoding heat shock proteins to human diseases: looking beyond the heat shock response. Dis Model Mech 7(4):421–434. doi:10.1242/dmm.014563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chhangani D, Mishra A (2013) Mahogunin ring finger-1 (MGRN1) suppresses chaperone-associated misfolded protein aggregation and toxicity. Sci Rep 3:1972. doi:10.1038/srep01972

    Article  PubMed  PubMed Central  Google Scholar 

  62. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171(4):603–614. doi:10.1083/jcb.200507002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G et al (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282(33):24131–24145. doi:10.1074/jbc.M702824200

    Article  CAS  PubMed  Google Scholar 

  64. Zatloukal K, Stumptner C, Fuchsbichler A, Heid H, Schnoelzer M, Kenner L, Kleinert R, Prinz M et al (2002) p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol 160(1):255–263. doi:10.1016/S0002-9440(10)64369-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275(21):16023–16029

    Article  CAS  PubMed  Google Scholar 

  66. Ishii T, Yanagawa T, Yuki K, Kawane T, Yoshida H, Bannai S (1997) Low micromolar levels of hydrogen peroxide and proteasome inhibitors induce the 60-kDa A170 stress protein in murine peritoneal macrophages. Biochem Biophys Res Commun 232(1):33–37. doi:10.1006/bbrc.1997.6221

    Article  CAS  PubMed  Google Scholar 

  67. Viiri J, Hyttinen JM, Ryhanen T, Rilla K, Paimela T, Kuusisto E, Siitonen A, Urtti A et al (2010) p62/sequestosome 1 as a regulator of proteasome inhibitor-induced autophagy in human retinal pigment epithelial cells. Mol Vis 16:1399–1414

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Robitaille Y, Lopes-Cendes I, Becher M, Rouleau G, Clark AW (1997) The neuropathology of CAG repeat diseases: review and update of genetic and molecular features. Brain Pathol 7(3):901–926

    Article  CAS  PubMed  Google Scholar 

  69. Donaldson KM, Li W, Ching KA, Batalov S, Tsai CC, Joazeiro CA (2003) Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc Natl Acad Sci U S A 100(15):8892–8897. doi:10.1073/pnas.1530212100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y et al (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9(14):2197–2202

    Article  CAS  PubMed  Google Scholar 

  71. Perez MK, Paulson HL, Pendse SJ, Saionz SJ, Bonini NM, Pittman RN (1998) Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 143(6):1457–1470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yamanaka T, Nukina N (2010) Transcription factor sequestration by polyglutamine proteins. Methods Mol Biol 648:215–229. doi:10.1007/978-1-60761-756-3_14

    Article  CAS  PubMed  Google Scholar 

  73. Sugars KL, Rubinsztein DC (2003) Transcriptional abnormalities in Huntington disease. Trends Genet 19(5):233–238. doi:10.1016/S0168-9525(03)00074-X

    Article  CAS  PubMed  Google Scholar 

  74. Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP et al (2000) The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A 97(12):6763–6768. doi:10.1073/pnas.100110097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yamanaka T, Miyazaki H, Oyama F, Kurosawa M, Washizu C, Doi H, Nukina N (2008) Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor. EMBO J 27(6):827–839. doi:10.1038/emboj.2008.23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Miller VM, Nelson RF, Gouvion CM, Williams A, Rodriguez-Lebron E, Harper SQ, Davidson BL, Rebagliati MR et al (2005) CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. J Neurosci : Off J Soc Neurosci 25(40):9152–9161. doi:10.1523/JNEUROSCI.3001-05.2005

    Article  CAS  Google Scholar 

  77. Ying Z, Wang H, Fan H, Zhu X, Zhou J, Fei E, Wang G (2009) Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation. Hum Mol Genet 18(22):4268–4281. doi:10.1093/hmg/ddp380

    Article  CAS  PubMed  Google Scholar 

  78. Yang H, Zhong X, Ballar P, Luo S, Shen Y, Rubinsztein DC, Monteiro MJ, Fang S (2007) Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin. Exp Cell Res 313(3):538–550. doi:10.1016/j.yexcr.2006.10.031

    Article  CAS  PubMed  Google Scholar 

  79. Mishra A, Dikshit P, Purkayastha S, Sharma J, Nukina N, Jana NR (2008) E6-AP promotes misfolded polyglutamine proteins for proteasomal degradation and suppresses polyglutamine protein aggregation and toxicity. J Biol Chem 283(12):7648–7656. doi:10.1074/jbc.M706620200

    Article  CAS  PubMed  Google Scholar 

  80. Barsh G, Gunn T, He L, Schlossman S, Duke-Cohan J (2000) Biochemical and genetic studies of pigment-type switching. Pigment Cell Res 13(Suppl 8):48–53

    Article  PubMed  Google Scholar 

  81. Hida T, Wakamatsu K, Sviderskaya EV, Donkin AJ, Montoliu L, Lynn Lamoreux M, Yu B, Millhauser GL et al (2009) Agouti protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathway. Pigment Cell Melanoma Res 22(5):623–634. doi:10.1111/j.1755-148X.2009.00582.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Barsh GS (2007) Regulation of pigment type switching by agouti, melanocortin signaling, attractin, and mahoganoid. In: The Pigmentary System: Physiology and Pathophysiology: Second Edition. pp 395–409. doi:10.1002/9780470987100.ch19

  83. Walker WP, Gunn TM (2009) Piecing together the pigment-type switching puzzle. Pigment Cell Melanoma Res 23(1):4–6. doi:10.1111/j.1755-148X.2009.00654.x

    Article  PubMed  Google Scholar 

  84. Bahr BA, Bendiske J (2002) The neuropathogenic contributions of lysosomal dysfunction. J Neurochem 83(3):481–489

    Article  CAS  PubMed  Google Scholar 

  85. Kurz T, Terman A, Gustafsson B, Brunk UT (2008) Lysosomes in iron metabolism, ageing and apoptosis. Histochem Cell Biol 129(4):389–406. doi:10.1007/s00418-008-0394-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH, Nixon RA (2008) Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci : Off J Soc Neurosci 28(27):6926–6937. doi:10.1523/JNEUROSCI.0800-08.2008

    Article  CAS  Google Scholar 

  87. Kirkegaard T, Roth AG, Petersen NH, Mahalka AK, Olsen OD, Moilanen I, Zylicz A, Knudsen J et al (2010) Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. Nature 463(7280):549–553. doi:10.1038/nature08710

    Article  CAS  PubMed  Google Scholar 

  88. Harbauer AB, Zahedi RP, Sickmann A, Pfanner N, Meisinger C (2014) The protein import machinery of mitochondria-a regulatory hub in metabolism, stress, and disease. Cell Metab 19(3):357–372. doi:10.1016/j.cmet.2014.01.010

    Article  CAS  PubMed  Google Scholar 

  89. Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58(4):495–505. doi:10.1002/ana.20624

    Article  CAS  PubMed  Google Scholar 

  90. Collignon J, Varlet I, Robertson EJ (1996) Relationship between asymmetric nodal expression and the direction of embryonic turning. Nature 381(6578):155–158. doi:10.1038/381155a0

    Article  CAS  PubMed  Google Scholar 

  91. Lowe LA, Supp DM, Sampath K, Yokoyama T, Wright CV, Potter SS, Overbeek P, Kuehn MR (1996) Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus. Nature 381(6578):158–161. doi:10.1038/381158a0

    Article  CAS  PubMed  Google Scholar 

  92. Meno C, Saijoh Y, Fujii H, Ikeda M, Yokoyama T, Yokoyama M, Toyoda Y, Hamada H (1996) Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos. Nature 381(6578):151–155. doi:10.1038/381151a0

    Article  CAS  PubMed  Google Scholar 

  93. Shiratori H, Hamada H (2006) The left-right axis in the mouse: from origin to morphology. Development 133(11):2095–2104. doi:10.1242/dev.02384

    Article  CAS  PubMed  Google Scholar 

  94. Yan YT, Gritsman K, Ding J, Burdine RD, Corrales JD, Price SM, Talbot WS, Schier AF et al (1999) Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev 13(19):2527–2537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cota CD, Bagher P, Pelc P, Smith CO, Bodner CR, Gunn TM (2006) Mice with mutations in Mahogunin ring finger-1 (Mgrn1) exhibit abnormal patterning of the left-right axis. Dev Dyn 235(12):3438–3447. doi:10.1002/dvdy.20992

    Article  CAS  PubMed  Google Scholar 

  96. Menzies FM, Fleming A, Rubinsztein DC (2015) Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci 16(6):345–357. doi:10.1038/nrn3961

    Article  CAS  PubMed  Google Scholar 

  97. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292(5521):1552–1555. doi:10.1126/science.292.5521.1552

    Article  CAS  PubMed  Google Scholar 

  98. Nau R, Sorgel F, Eiffert H (2010) Penetration of drugs through the blood-cerebrospinal fluid/blood–brain barrier for treatment of central nervous system infections. Clin Microbiol Rev 23(4):858–883. doi:10.1128/CMR.00007-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Pardridge WM (2011) Drug transport in brain via the cerebrospinal fluid. Fluids and barriers of the CNS 8(1):7. doi:10.1186/2045-8118-8-7

    Article  PubMed  PubMed Central  Google Scholar 

  100. Ohtsuka K, Kawashima D, Gu Y, Saito K (2005) Inducers and co-inducers of molecular chaperones. Int J Hyperth 21(8):703–711. doi:10.1080/02656730500384248

    Article  CAS  Google Scholar 

  101. Nagai Y, Fujikake N, Popiel HA, Wada K (2010) Induction of molecular chaperones as a therapeutic strategy for the polyglutamine diseases. Curr Pharm Biotechnol 11(2):188–197

    Article  CAS  PubMed  Google Scholar 

  102. Rokutan K (2003) Molecular chaperone inducers in medicine and diseases. Nihon Yakurigaku Zasshi 121(1):15–20

    Article  CAS  PubMed  Google Scholar 

  103. Lilienbaum A (2013) Relationship between the proteasomal system and autophagy. Int J Biochem Mol Biol 4(1):1–26

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D, Yin XM (2007) Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171(2):513–524. doi:10.2353/ajpath.2007.070188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Chhangani D, Chinchwadkar S, Mishra A (2014) Autophagy coupling interplay: can improve cellular repair and aging? Mol Neurobiol 49(3):1270–1281. doi:10.1007/s12035-013-8599-z

    Article  CAS  PubMed  Google Scholar 

  106. Raina K, Crews CM (2010) Chemical inducers of targeted protein degradation. J Biol Chem 285(15):11057–11060. doi:10.1074/jbc.R109.078105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Stone S, Hauksdóttir H, Troy A, Herschleb J, Kraft E, Callis J (2005) Functional analysis of the RING-type ubiquitin ligase family of Arabidopsis. Plant Physiol 137(1):13–30. doi:10.1104/pp.104.052423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H et al (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7:539. doi:10.1038/msb.2011.75

    Article  PubMed  PubMed Central  Google Scholar 

  109. Clamp M, Cuff J, Searle SM, Barton GJ (2004) The Jalview Java alignment editor. Bioinformatics 20(3):426–427. doi:10.1093/bioinformatics/btg430

    Article  CAS  PubMed  Google Scholar 

  110. Cooray SN, Guasti L, Clark AJ (2011) The E3 ubiquitin ligase Mahogunin ubiquitinates the melanocortin 2 receptor. Endocrinology 152(11):4224–4231. doi:10.1210/en.2011-0147

    Article  CAS  PubMed  Google Scholar 

  111. Gunn TM, Silvius D, Bagher P, Sun K, Walker KK (2013) MGRN1-dependent pigment-type switching requires its ubiquitination activity but not its interaction with TSG101 or NEDD4. Pigment Cell Melanoma Res 26(2):263–268. doi:10.1111/pcmr.12059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chhangani D, Nukina N, Kurosawa M, Amanullah A, Joshi V, Upadhyay A, Mishra A (2014) Mahogunin ring finger 1 suppresses misfolded polyglutamine aggregation and cytotoxicity. Biochim Biophys Acta 1842(9):1472–1484. doi:10.1016/j.bbadis.2014.04.014

    Article  CAS  PubMed  Google Scholar 

  113. Srivastava D, Chakrabarti O (2014) Mahogunin-mediated alpha-tubulin ubiquitination via noncanonical K6 linkage regulates microtubule stability and mitotic spindle orientation. Cell Death Dis 5, e1064. doi:10.1038/cddis.2014.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Cheng D, Xiong C, Li J, Sui C, Wang S, Li H, Jiang X (2014) The effect of mahogunin gene mutant on reproduction in male mice: a new sight for infertility? Andrologia 46(2):98–105. doi:10.1111/and.12050

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Department of Biotechnology, Government of India. AM was supported by Ramalinganswami Fellowship (BT/RLF/Reentry/11/2010) and Innovative Young Biotechnologist Award (IYBA) scheme (BT/06/IYBA/2012) from the Department of Biotechnology, Government of India. AU was supported by a research fellowship from the Council of Scientific and Industrial Research-University Grants Commission (CSIR-UGC), Government of India. The authors would like to thank Mr. Bharat Pareek for his technical assistance and the entire lab management during the manuscript preparation. We apologize to various authors whose work could not be included due to space limitations.

Compliance with Ethical Requirements

ᅟ

Conflict of Interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, 342011, India

    Arun Upadhyay, Ayeman Amanullah, Deepak Chhangani, Ribhav Mishra & Amit Mishra

  2. School of Basic Sciences, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh, 175005, India

    Amit Prasad

Authors
  1. Arun Upadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayeman Amanullah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deepak Chhangani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ribhav Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amit Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amit Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amit Mishra.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Upadhyay, A., Amanullah, A., Chhangani, D. et al. Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms. Mol Neurobiol 53, 4484–4496 (2016). https://doi.org/10.1007/s12035-015-9379-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9379-8

Keywords

Search

Navigation