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Defining the Proteostasis Network Responsible for Managing the Fate of Newly Synthesized Alpha1-Antitrypsin

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The Serpin Family

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Abstract

Alpha1-antitrypsin (AAT) is a serine proteinase inhibitor (serpin) secreted from hepatocytes. Its normal circulating concentration in the bloodstream is sufficient to prevent the destruction of lung elastin fibers by excessive elastase released from activated neutrophils, thereby maintaining the organ’s elasticity and function. Many naturally occurring genetic variants of AAT, unable to acquire correct structural maturation following biosynthesis, are subjected to intracellular proteolysis in the hepatocyte secretory pathway. This, in turn, can contribute to the development of chronic obstructive pulmonary disease. In addition, the inappropriate accumulation of structurally aberrant AAT within hepatocytes can contribute to the etiology of liver disease. The mechanistic analysis of intracellular systems that manage AAT fate has led to the identification of dedicated systems that facilitate proper polypeptide folding and orchestrate the selective elimination of molecules that fail to acquire conformational maturation. These systems, which contribute to the diverse cellular proteostasis network, are expected to aid in the identification of disease modifiers and development of novel strategies for therapeutic intervention of the lung and liver diseases, as well as additional conformational disorders that involve the secretory pathway. This review focuses on the discovery and characterization of proteostasis systems that operate in the secretory pathway that selectively eliminate different forms of structurally aberrant AAT.

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References

  • Balch WE, Morimoto RI et al (2008) Adapting proteostasis for disease intervention. Science 319(5865):916–919

    Article  CAS  PubMed  Google Scholar 

  • Bernasconi R, Molinari M (2011) ERAD and ERAD tuning: disposal of cargo and of ERAD regulators from the mammalian ER. Curr Opin Cell Biol 23(2):176–183

    Article  CAS  PubMed  Google Scholar 

  • Bernasconi R, Pertel T et al (2008) A dual task for the Xbp1-responsive OS-9 variants in the mammalian endoplasmic reticulum: inhibiting secretion of misfolded protein conformers and enhancing their disposal. J Biol Chem 283(24):16446–16454

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bernasconi R, Galli C et al (2010) Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates. J Cell Biol 188(2):223–235

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bonifacino JS, Weissman AM (1998) Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annu Rev Cell Dev Biol 14:19–57

    Article  CAS  PubMed  Google Scholar 

  • Brodsky JL (2012) Cleaning up: ER-associated degradation to the rescue. Cell 151(6):1163–1167

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cabral CM, Choudhury P et al (2000) Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways. J Biol Chem 275(32):25015–25022

    Article  CAS  PubMed  Google Scholar 

  • Cabral CM, Liu Y et al (2001) Dissecting glycoprotein quality control in the secretory pathway. Trends Biochem Sci 26(10):619–624

    Article  CAS  PubMed  Google Scholar 

  • Cabral CM, Liu Y et al (2002) Organizational diversity among distinct glycoprotein endoplasmic reticulum-associated degradation programs. Mol Biol Cell 13(8):2639–2650

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Caldwell SR, Hill KJ et al (2001) Degradation of endoplasmic reticulum (ER) quality control substrates requires transport between the ER and Golgi. J Biol Chem 276(26):23296–23303

    Article  CAS  PubMed  Google Scholar 

  • Cali T, Vanoni O et al (2008) The endoplasmic reticulum crossroads for newly synthesized polypeptide chains. Prog Mol Biol Transl Sci 83:135–179

    Article  CAS  PubMed  Google Scholar 

  • Carlson JA, Rogers BB et al (1989) Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J Clin Invest 83(4):1183–1190

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Carrell R, Lomas D et al (1997) Dysfunctional variants and the structural biology of the serpins. Adv Exp Med Biol 425:207–222

    Article  CAS  PubMed  Google Scholar 

  • Christianson JC, Olzmann JA et al (2011) Defining human ERAD networks through an integrative mapping strategy. Nat Cell Biol 14(1):93–105

    Article  PubMed Central  PubMed  Google Scholar 

  • Crowther DC, Belorgey D et al (2004) Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. Eur J Hum Genet 12(3):167–172

    Article  CAS  PubMed  Google Scholar 

  • Ellgaard L, Helenius A (2001) ER quality control: towards an understanding at the molecular level. Curr Opin Cell Biol 13(4):431–437

    Article  CAS  PubMed  Google Scholar 

  • Ellgaard L, Molinari M et al (1999) Setting the standards: quality control in the secretory pathway. Science 286(5446):1882–1888

    Article  CAS  PubMed  Google Scholar 

  • Eriksson S (1965) Studies in alpha 1-antitrypsin deficiency. Acta Med Scand Suppl 432:1–85

    CAS  PubMed  Google Scholar 

  • Fewell SW, Travers KJ et al (2001) The action of molecular chaperones in the early secretory pathway. Annu Rev Genet 35:149–191

    Article  CAS  PubMed  Google Scholar 

  • Gething MJ, Sambrook J (1992) Protein folding in the cell. Nature 355(6355):33–45

    Article  CAS  PubMed  Google Scholar 

  • Gilchrist A, Au CE et al (2006) Quantitative proteomics analysis of the secretory pathway. Cell 127(6):1265–1281

    Article  CAS  PubMed  Google Scholar 

  • Graham KS, Le A et al (1990) Accumulation of the insoluble PiZ variant of human alpha 1-antitrypsin within the hepatic endoplasmic reticulum does not elevate the steady-state level of grp78/BiP. J Biol Chem 265(33):20463–20468

    CAS  PubMed  Google Scholar 

  • Hammond C, Helenius A (1995) Quality control in the secretory pathway. Curr Opin Cell Biol 7(4):523–529

    Article  CAS  PubMed  Google Scholar 

  • Helenius A, Marquardt T et al (1992) The endoplasmic reticulum as a protein-folding compartment. Trends Cell Biol 2(8):227–231

    Article  CAS  PubMed  Google Scholar 

  • Hidvegi T, Schmidt BZ et al (2005) Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response. J Biol Chem 280(47):39002–39015

    Article  CAS  PubMed  Google Scholar 

  • Hidvegi T, Ewing M et al (2010) An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 329(5988):229–232

    Article  CAS  PubMed  Google Scholar 

  • Hosokawa N, Tremblay LO et al (2003) Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I. J Biol Chem 278(28):26287–26294

    Article  CAS  PubMed  Google Scholar 

  • Hosokawa N, You Z et al (2007) Stimulation of ERAD of misfolded null Hong Kong alpha1-antitrypsin by Golgi alpha1,2-mannosidases. Biochem Biophys Res Commun 362(3):626–632

    Article  CAS  PubMed  Google Scholar 

  • Hutt DM, Powers ET et al (2009) The proteostasis boundary in misfolding diseases of membrane traffic. FEBS Lett 583(16):2639–2646

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Iannotti MJ, Figard L et al (2014) A Golgi-localized mannosidase (MAN1B1) plays a non-enzymatic gatekeeper role in protein biosynthetic quality control. J Biol Chem 289(17):11844–11858

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Karaveg K, Siriwardena A et al (2005) Mechanism of class 1 (glycosylhydrolase family 47) {alpha}-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control. J Biol Chem 280(16):16197–16207

    Article  CAS  PubMed  Google Scholar 

  • Klausner RD, Sitia R (1990) Protein degradation in the endoplasmic reticulum. Cell 62(4):611–614

    Article  CAS  PubMed  Google Scholar 

  • Le A, Graham KS et al (1990) Intracellular degradation of the transport-impaired human PiZ alpha 1-antitrypsin variant. Biochemical mapping of the degradative event among compartments of the secretory pathway. J Biol Chem 265(23):14001–14007

    CAS  PubMed  Google Scholar 

  • Le A, Ferrell GA et al (1992) Soluble aggregates of the human PiZ alpha 1-antitrypsin variant are degraded within the endoplasmic reticulum by a mechanism sensitive to inhibitors of protein synthesis. J Biol Chem 267(2):1072–1080

    CAS  PubMed  Google Scholar 

  • Liu Y, Choudhury P et al (1997) Intracellular disposal of incompletely folded human alpha1-antitrypsin involves release from calnexin and post-translational trimming of asparagine-linked oligosaccharides. J Biol Chem 272(12):7946–7951

    Article  CAS  PubMed  Google Scholar 

  • Lomas DA, Mahadeva R (2002) Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest 110(11):1585–1590

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lomas DA, Evans DL et al (1992) The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357(6379):605–607

    Article  CAS  PubMed  Google Scholar 

  • Molinari M (2007) N-glycan structure dictates extension of protein folding or onset of disposal. Nat Chem Biol 3(6):313–320

    Article  CAS  PubMed  Google Scholar 

  • Ninagawa S, Okada T et al (2014) EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step. J Cell Biol 206(3):347–356

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Olivari S, Molinari M (2007) Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation of folding-defective glycoproteins. FEBS Lett 581(19):3658–3664

    Article  CAS  PubMed  Google Scholar 

  • Pan S, Huang L et al (2009) Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency. Hepatology 50(1):275–281

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pan S, Wang S et al (2011) Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system. Mol Biol Cell 22(16):2810–2822

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pan S, Cheng X et al (2013) Golgi-situated endoplasmic reticulum alpha-1, 2-mannosidase contributes to the retrieval of ERAD substrates through a direct interaction with gamma-COP. Mol Biol Cell 24(8):1111–1121

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Parmar JS, Mahadeva R et al (2002) Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema. Am J Respir Cell Mol Biol 26(6):723–730

    Article  CAS  PubMed  Google Scholar 

  • Perlmutter DH (1991) The cellular basis for liver injury in alpha 1-antitrypsin deficiency. Hepatology 13(1):172–185

    Article  CAS  PubMed  Google Scholar 

  • Perlmutter DH (1993) Liver disease associated with alpha 1-antitrypsin deficiency. Prog Liver Dis 11:139–165

    CAS  PubMed  Google Scholar 

  • Perlmutter DH (2000) Liver injury in alpha 1-antitrypsin deficiency. Clin Liver Dis 4(2):387–408, vi

    Article  CAS  PubMed  Google Scholar 

  • Perlmutter DH (2006) Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res 60(2):233–238

    Article  CAS  PubMed  Google Scholar 

  • Plemper RK, Wolf DH (1999) Endoplasmic reticulum degradation. Reverse protein transport and its end in the proteasome. Mol Biol Rep 26(1–2):125–130

    Article  CAS  PubMed  Google Scholar 

  • Qu D, Teckman JH et al (1996) Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J Biol Chem 271(37):22791–22795

    Article  CAS  PubMed  Google Scholar 

  • Qu D, Teckman JH et al (1997) Review: alpha 1-antitrypsin deficiency associated liver disease. J Gastroenterol Hepatol 12(5):404–416

    Article  CAS  PubMed  Google Scholar 

  • Rafiq MA, Kuss AW et al (2011) Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability. Am J Hum Genet 89(1):176–182

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Reggiori F, Monastyrska I et al (2010) Coronaviruses Hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe 7(6):500–508

    Article  CAS  PubMed  Google Scholar 

  • Rymen D, Peanne R et al (2013) MAN1B1 deficiency: an unexpected CDG-II. PLoS Genet 9(12), e1003989

    Article  PubMed Central  PubMed  Google Scholar 

  • Satoh T, Chen Y et al (2010) Structural basis for oligosaccharide recognition of misfolded glycoproteins by OS-9 in ER-associated degradation. Mol Cell 40(6):905–916

    Article  CAS  PubMed  Google Scholar 

  • Shen X, Ellis RE et al (2001) Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 107(7):893–903

    Article  CAS  PubMed  Google Scholar 

  • Sifers RN (2010) Intracellular processing of alpha1-antitrypsin. Proc Am Thorac Soc 7(6):376–380

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sifers RN, Brashears-Macatee S et al (1988) A frameshift mutation results in a truncated alpha 1-antitrypsin that is retained within the rough endoplasmic reticulum. J Biol Chem 263(15):7330–7335

    CAS  PubMed  Google Scholar 

  • Sifers RN, Finegold MJ et al (1989) Alpha-1-antitrypsin deficiency: accumulation or degradation of mutant variants within the hepatic endoplasmic reticulum. Am J Respir Cell Mol Biol 1(5):341–345

    Article  CAS  PubMed  Google Scholar 

  • Sifers RN, Finegold MJ et al (1992) Molecular biology and genetics of alpha 1-antitrypsin deficiency. Semin Liver Dis 12(3):301–310

    Article  CAS  PubMed  Google Scholar 

  • Sousa MC, Ferrero-Garcia MA et al (1992) Recognition of the oligosaccharide and protein moieties of glycoproteins by the UDP-Glc:glycoprotein glucosyltransferase. Biochemistry 31(1):97–105

    Article  CAS  PubMed  Google Scholar 

  • Teckman JH, Perlmutter DH (1996) The endoplasmic reticulum degradation pathway for mutant secretory proteins alpha1-antitrypsin Z and S is distinct from that for an unassembled membrane protein. J Biol Chem 271(22):13215–13220

    Article  CAS  PubMed  Google Scholar 

  • Teckman JH, Perlmutter DH (2000) Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol Gastrointest Liver Physiol 279(5):G961–G974

    CAS  PubMed  Google Scholar 

  • Teckman JH, Burrows J et al (2001) The proteasome participates in degradation of mutant alpha 1-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes. J Biol Chem 276(48):44865–44872

    Article  CAS  PubMed  Google Scholar 

  • Teckman JH, An JK et al (2004) Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol 286(5):G851–G862

    Article  CAS  PubMed  Google Scholar 

  • Volpert D, Molleston JP et al (2000) Alpha1-antitrypsin deficiency-associated liver disease progresses slowly in some children. J Pediatr Gastroenterol Nutr 31(3):258–263

    Article  CAS  PubMed  Google Scholar 

  • Wu Y, Whitman I et al (1994) A lag in intracellular degradation of mutant alpha 1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha 1-antitrypsin deficiency. Proc Natl Acad Sci USA 91(19):9014–9018

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wu Y, Swulius MT et al (2003) Elucidation of the molecular logic by which misfolded alpha 1-antitrypsin is preferentially selected for degradation. Proc Natl Acad Sci USA 100(14):8229–8234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wu Y, Termine DJ et al (2007) Human endoplasmic reticulum mannosidase I is subject to regulated proteolysis. J Biol Chem 282(7):4841–4849

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yoshida H, Matsui T et al (2003) A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell 4(2):265–271

    Article  CAS  PubMed  Google Scholar 

  • Yu MH, Lee KN et al (1995) The Z type variation of human alpha 1-antitrypsin causes a protein folding defect. Nat Struct Biol 2(5):363–367

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA

    Richard N. Sifers

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  1. Richard N. Sifers
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Correspondence to Richard N. Sifers .

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Editors and Affiliations

  1. Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Margarethe Geiger

  2. Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Felix Wahlmüller

  3. Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Margareta Furtmüller

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Sifers, R.N. (2015). Defining the Proteostasis Network Responsible for Managing the Fate of Newly Synthesized Alpha1-Antitrypsin. In: Geiger, M., Wahlmüller, F., Furtmüller, M. (eds) The Serpin Family. Springer, Cham. https://doi.org/10.1007/978-3-319-22711-5_13

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