Abstract
In the classical form of α1-antitrypsin deficiency (ATD) a point mutation leads to accumulation of a misfolded secretory glycoprotein in the endoplasmic reticulum (ER) of liver cells and so ATD has come to be considered a prototypical ER storage disease . It is associated with two major types of clinical disorders, chronic obstructive pulmonary disease (COPD) by lossof- function mechanisms and hepatic cirrhosis and carcinogenesis by gain-of-function mechanisms. The lung disease predominantly results from proteolytic damage to the pulmonary connective tissue matrix because of reduced levels of protease inhibitor activity of α1-anitrypsin (AT) in the circulating blood and body fluids. Cigarette smoking is a powerful disease-promoting modifier but other modifiers are known to exist because variation in the lung disease phenotype is still found in smoking and non-smoking homozygotes. The liver disease is highly likely to be caused by the proteotoxic effects of intracellular misfolded protein accumulation and a high degree of variation in the hepatic phenotype among affected homozygotes has been hypothetically attributed to genetic and environmental modifiers that alter proteostasis responses. Liver biopsies of homozygotes show intrahepatocytic inclusions with dilation and expansion of the ER and recent studies of iPS-derived hepatocyte-like cells from individuals with ATD indicate that the changes in the ER directly vary with the hepatic phenotype i.e there is much lesser alteration in the ER in cells derived from homozygotes that do not have clinically significant liver disease. From a signaling perspective, studies in mammalian cell line and animal models expressing the classical α1-antitrypsin Z variant (ATZ) have found that ER signaling is perturbed in a relatively unique way with powerful activation of autophagy and the NFκB pathway but relatively limited, if any, UPR signaling. It is still not known how much these unique structural and functional changes and the variation among affected homozygotes relate to the tendency of this variant to polymerize and aggregate and/ or to the repertoire of proteostasis mechanisms that are activated.
References
[1] Laurell C-B, Eriksson S. The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15: 132-40. 10.1080/00365516309051324Search in Google Scholar
[2] Brantly ML, Paul LD, Miller BH, et al. Clinical features and history of the destructive lung disease associated with alpha- 1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis 1988;128:327–36. 10.1164/ajrccm/138.2.327Search in Google Scholar
[3] Janus ED, Philips NT, Carrell RW. Smoking, lung function and α1-antitrypsin deficiency. Lancet 1985;1:152–4. 10.1016/S0140-6736(85)91916-6Search in Google Scholar
[4] Sharp HL, Bridges RA, Krivit W, Freier EF. Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder. J Lab Clin Med. 1969;73:934–939. Search in Google Scholar
[5] Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha1-antitrypsin deficiency. N Engl J Med. 1986;314:736–739. 10.1056/NEJM198603203141202Search in Google Scholar PubMed
[6] Chu AS, Chopra KB, Perlmutter DH. Is severe progressive liver disease caused by α1-antitrypsin deficiency more common in children or adults? Liver Transplantation 2016; 22: 886-94. 10.1002/lt.24434Search in Google Scholar PubMed
[7] Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med. 1976;294:1316–1321. 10.1056/NEJM197606102942404Search in Google Scholar PubMed
[8] Tanash HA, Nystedt-Duzakin M, Montero LC, Sveger T, Piitulainen E. The Swedish α1-antitrypsin screening study: Health status and lung and liver function at age 34. Ann Am Thorac Soc 2015; 12: 807-12 10.1513/AnnalsATS.201410-452OCSearch in Google Scholar PubMed
[9] Perlmutter DH. Alpha-1-antitrypsin deficiency: Importance of proteasomal and autophagic degradative pathways in disposal of liver disease–associated protein aggregates. Annu Rev Med. 2011;62:333–345. 10.1146/annurev-med-042409-151920Search in Google Scholar PubMed
[10] Teckman JH, Qu D, Perlmutter DH. Molecular pathogenesis of liver disease in α1-antitrypsin deficiency. Hepatology. 1996;24:1504–16. Search in Google Scholar
[11] Doppler K, Mittelbron M, Lindner A, Bornemann A. Basement membrane remodeling and segmental fibrosis in sporadic inclusion body myositis. Neuromuscul Disord. 2009; 19 (6): 406-411. 10.1016/j.nmd.2009.04.011Search in Google Scholar PubMed
[12] Shenuarin Bhuiyan MD, Pattison JS, Osinska H, et al. Enhanced autophagy ameliorates cardiac proteinopathy. J Clin Invest. 2013; 123 (12): 5284-5297. 10.1172/JCI70877Search in Google Scholar PubMed PubMed Central
[13] Lawson WE, Cheng DS, Degryse AL, et al. Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. Proc Natl Acad Sci USA. 2011; 108 (26): 10562-10567. 10.1073/pnas.1107559108Search in Google Scholar
[14] Young LR, Gulleman PM, Bridges JP, et al. The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky-Pudlak syndrome. Am J Respir Crit Care Med. 2012; 186 (10): 1014-1024. 10.1164/rccm.201207-1206OCSearch in Google Scholar
[15] Rudnick DA, Perlmutter DH. Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology 2005; 42: 514-21. 10.1002/hep.20815Search in Google Scholar
[16] Tafaleng EN, Han, B., Hale, P., Chakraborty, S., Soto-Gutierrez, A., Feghali-Bostwick, C., Kotton, Nagaya, Duncan, A.D., Stolz, D.B., Strom, Chowdhury, J.R., Perlmutter, D.H., Fox, I.J. The rate of disappearance of intracellular α1 antitrypsin correlates with liver disease severity in iPSc-derived hepatocytes generated from PIZZ α-1-antitrypsin deficiency. Hepatology. 2013;58:81A. Search in Google Scholar
[17] Silverman EK, Sandhaus RA. Clinical practice. Alpha1- antitrypsin deficiency. N Engl J Med 2009;360:2749–57. 10.1056/NEJMcp0900449Search in Google Scholar
[18] Hidvegi T, Stolz DB, Alcorn JF, Yousem SA, Wang J, Leme AS et al. Enhancing autophagy with drugs or lung-directed gene therapy reverses the pathological effects of respiratory epithelial cell proteinopathy. J Biol Chem 2015; 290: 29742-57. 10.1074/jbc.M115.691253Search in Google Scholar
[19] Wu Y, Foreman RC. The effect of amino acid substitutions at position 342 on the secretion of human alpha 1-antitrypsin from Xenopus oocytes. FEBS letter. 1990;268:21-31 10.1016/0014-5793(90)80962-ISearch in Google Scholar
[20] Perlmutter DH, Kay RM, Cole FS, Rossing TH, Van Thiel D, Colten HR. The cellular defect in alpha 1-proteinase inhibitor (alpha 1-PI) deficiency is expressed in human monocytes and in Xenopus oocytes injected with human liver mRNA. Proc Natl Acad Sci U S A. 1985;82:6918-6921. 10.1073/pnas.82.20.6918Search in Google Scholar PubMed PubMed Central
[21] Wu Y, Whitman I, Molmenti E, Moore K, Hippenmeyer P, Perlmutter DH. 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 U S A. 1994;91:9014-9018. 10.1073/pnas.91.19.9014Search in Google Scholar PubMed PubMed Central
[22] Long OS, Benson JA, Kwak JH, Luke CJ, Gosai SJ, O’Reilly LP, et al. A C. elegans model of human alpha1-antitrypsin deficiency links components of the RNAi pathway to misfolded protein turnover. Hum Molec Genet. 2014;23:5109-5122. 10.1093/hmg/ddu235Search in Google Scholar PubMed PubMed Central
[23] Lin L, Schmidt B, Teckman J, Perlmutter DH. A naturally occurring nonpolymerogenic mutant of alpha 1-antitrypsin characterized by prolonged retention in the endoplasmic reticulum. J Biol Chem. 2001;276:33893-33898. 10.1074/jbc.M105226200Search in Google Scholar PubMed
[24] Schmidt BZ, Perlmutter DH. Grp78, Grp94, and Grp170 interact with alpha1-antitrypsin mutants that are retained in the endoplasmic reticulum. Am J Physiol. 2005;289:G444-455. 10.1152/ajpgi.00237.2004Search in Google Scholar PubMed
[25] Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH. 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. 2005;280:39002- 39015. 10.1074/jbc.M508652200Search in Google Scholar PubMed
[26] Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature. 1992;357:605-607. 10.1038/357605a0Search in Google Scholar PubMed
[27] Sidhar SK, Lomas DA, Carrell RW, Foreman RC. Mutations which impede loop/sheet polymerization enhance the secretion of human alpha 1-antitrypsin deficiency variants. J Biol Chem. 1995;270:8393-8396. 10.1074/jbc.270.15.8393Search in Google Scholar PubMed
[28] Yamasaki M, Li W, Johnson DJ, Huntington JA. Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature. 2008;455:1255-1258. 10.1038/nature07394Search in Google Scholar PubMed
[29] Whisstock JC, Silverman GA, Bird PI, Bottomley SP, Kaiserman D, Luke CJ, et al. Serpins flex their muscle: II. Structural insights into target peptidase recognition, polymerization, and transport functions. J Biol Chem. 2010;285:24307-24312. 10.1074/jbc.R110.141408Search in Google Scholar PubMed PubMed Central
[30] Yamasaki M, Sendall TJ, Pearce MC, Whisstock JC, Huntington JA. Molecular basis of alpha1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer. EMBO Rep. 2011;12:1011-1017. 10.1038/embor.2011.171Search in Google Scholar PubMed PubMed Central
[31] Huang X, Zheng Y, Zhang F, Wei Z, Wang Y, Carrell RW, et al. Molecular mechanism of Z α1-antitrypsin deficiency. J Biol Chem 2016; 291: 15674-86. 10.1074/jbc.M116.727826Search in Google Scholar PubMed PubMed Central
[32] Mallya M, Phillips RL, Saldanha SA, Gooptu B, Brown SC, Termine DJ, et al. Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates. J Med Chem. 2007;50:5357-5363. 10.1021/jm070687zSearch in Google Scholar PubMed PubMed Central
[33] Nyfeler B, Reiterer V, Wendeler MW, et al. Identification of ERGIC-53 as an intracellular transport receptor of α1-antitrypsin. J Cell Biol 2008;180:705–12. 10.1083/jcb.200709100Search in Google Scholar PubMed PubMed Central
[34] Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, et al. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell. 2009;139:1157-1169. 10.1016/j.cell.2009.11.014Search in Google Scholar PubMed PubMed Central
[35] Qu D, Teckman JH, Omura S, Perlmutter DH. Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J Biol Chem. 1996;271:22791-22795. 10.1074/jbc.271.37.22791Search in Google Scholar PubMed
[36] Teckman JH, Burrows J, Hidvegi T, Schmidt B, Hale PD, Perlmutter DH. The proteasome participates in degradation of mutant alpha 1-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes. J Biol Chem. 2001;276:44865- 44872. 10.1074/jbc.M103703200Search in Google Scholar PubMed
[37] Werner ED, Brodsky JL, McCracken AA. Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. Proc Natl Acad Sci U S A. 1996;93:13797-13801. 10.1073/pnas.93.24.13797Search in Google Scholar PubMed PubMed Central
[38] Brodsky JL, Wojcikiewicz RJ. Substrate-specific mediators of ER associated degradation (ERAD). Current Opin Cell Biol. 2009;21:516-521. 10.1016/j.ceb.2009.04.006Search in Google Scholar PubMed PubMed Central
[39] Teckman JH, Perlmutter DH. Retention of mutant alpha(1)- antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol. 2000;279:G961-G974. 10.1152/ajpgi.2000.279.5.G961Search in Google Scholar PubMed
[40] Kamimoto T, Shoji S, Hidvegi T, Mizushima N, Umebayashi K, Perlmutter DH, et al. Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem. 2006;281:4467-4476. 10.1074/jbc.M509409200Search in Google Scholar PubMed
[41] Kruse KB, Brodsky JL, McCracken AA. Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human alpha-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ. Mol Biol Cell. 2006;17:203-212. 10.1091/mbc.e04-09-0779Search in Google Scholar PubMed PubMed Central
[42] Kruse KB, Dear A, Kaltenbrun ER, Crum BE, George PM, Brennan SO, et al. Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. Am J Pathol. 2006;168:1299-1308. 10.2353/ajpath.2006.051097Search in Google Scholar PubMed PubMed Central
[43] Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science. 2010;329:229-232. 10.1126/science.1190354Search in Google Scholar PubMed
[44] Li J, Pak SC, O’Reilly LP, Benson JA, Wang Y, Hidvegi T, et al. Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of alpha-1-antitrypsin deficiency. PloS One. 2014;9:e87260. 10.1371/journal.pone.0087260Search in Google Scholar PubMed PubMed Central
[45] O’Reilly LP, Benson JA, Cummings EE, Perlmutter DH, Silverman GA, Pak SC. Worming our way to novel drug discovery with the Caenorhabditis elegans proteostasis network, stress response and insulin-signaling pathways. Expert Opin Drug Discov. 2014;9:1021-1032 10.1517/17460441.2014.930125Search in Google Scholar PubMed
[46] Gelling CL, Dawes IW, Perlmutter DH, Fisher EA, Brodsky JL. The endosomal protein-sorting receptor sortilin has a role in trafficking alpha-1 antitrypsin. Genetics. 2012;192:889-903. 10.1534/genetics.112.143487Search in Google Scholar PubMed PubMed Central
[47] Kamimoto T, Shoji S, Mizushima N, et al. The intracellular inclusions containing mutant α-1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem2006;281:4467–76. 10.1074/jbc.M509409200Search in Google Scholar PubMed
[48] Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH. Accumulation of mutant α1-antitrypsin Z in the ER activates caspases-4 and -12, NFκB and BAP31 but not the unfolded protein response. J Biol Chem 2005;280:39002–15. 10.1074/jbc.M508652200Search in Google Scholar PubMed
[49] Hidvegi T, Mirnics K, Hale P, Ewing M, Beckett C, Perlmutter DH. Regulator of G signaling 16 is a marker for the distinct endoplasmic reticulum stress state associated with aggregated mutant α1-antitrypsin Z in the classical form of α1-antitrypsin deficiency. J Biol Chem 2007;282:27769–80. 10.1074/jbc.M704330200Search in Google Scholar PubMed
[50] Liao Y, Shikapwashya ON, Shteyer E, Dieckgraefe BK, Hruz PW, Rudnick DA. Delayed hepatocellular mitotic progression and impaired liver regeneration in early growth response-1- deficient mice. J Biol Chem2004;279:43107–16. 10.1074/jbc.M407969200Search in Google Scholar PubMed
[51] Gohla A, Klement K, Piekorz RP, et al. An obligatory requirement for the heterotrimeric G protein Gαi3 in the antiautophagic action of insulin in the liver. Proc Natl Acad Sci USA 2007;104:3003–8. 10.1073/pnas.0611434104Search in Google Scholar PubMed PubMed Central
[52] Yunis E, Agostini R, Glew R. Fine structural observations of the liver in alpha-1-antitrypsin deficiency. Am J Pathol 1976; 82: 265-86. Search in Google Scholar
[53] Hultcrantz R, Mengarelli S. Ultrastructural liver pathology in patients with minimal liver disease Hepatology 1983; 4: 937-45. 10.1002/hep.1840040526Search in Google Scholar PubMed
[54] Wolff S, Weissman J, Dillin A. Differential scales of protein quality control. Cell 2014; 157: 52-64. 10.1016/j.cell.2014.03.007Search in Google Scholar PubMed
[55] Pan S, Huang L, McPherson J, Muzny D, Rouhani F, Brantly M, et al. Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency. Hepatology. 2009;50:275-281. 10.1002/hep.22974Search in Google Scholar PubMed PubMed Central
[56] Pan S, Wang S, Utama B, Huang L, Blok N, Estes MK, et al. Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system. Mol Biol Cell. 2011;22:2810-2822. 10.1091/mbc.e11-02-0118Search in Google Scholar PubMed PubMed Central
[57] Iannotti MJ, Figard L, Sokac AM, Sifers RN. A Golgi-localized mannosidase (MAN1B1) plays a non-enzymatic gatekeeper role in protein biosynthetic quality control. J Biol Chem. 2014;289:11844-11858. 10.1074/jbc.M114.552091Search in Google Scholar PubMed PubMed Central
[58] Chappell S, Guetta-Baranes T, Hadzic N, Stockley R, Kalsheker N. Polymorphism in the endoplasmic reticulum mannosidase I (MAN1B1) gene is not associated with liver disease in individuals homozygous for the Z variant of the alpha1- antitrypsin protease inhibitor (PiZZ individuals). Hepatology. 2009;50:1315. 10.1002/hep.23170Search in Google Scholar PubMed
[59] Chappell S, Hadzic N, Stockley R, Guetta-Baranes T, Morgan K, Kalsheker N. A polymorphism of the alpha1-antitrypsin gene represents a risk factor for liver disease. Hepatology. 2008;47:127-132. 10.1002/hep.21979Search in Google Scholar PubMed
© 2016 David H Perlmutter
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