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Defects in Protein Folding and/or Quality Control Cause Protein Aggregation in the Endoplasmic Reticulum

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Cellular Biology of the Endoplasmic Reticulum

Part of the book series: Progress in Molecular and Subcellular Biology ((PMSB,volume 59))

Abstract

Protein aggregation is now a common hallmark of numerous human diseases, most of which involve cytosolic aggregates including Aβ (AD) and ⍺-synuclein (PD) in Alzheimer’s disease and Parkinson’s disease. However, it is also evident that protein aggregation can also occur in the lumen of the endoplasmic reticulum (ER) that leads to specific diseases due to loss of protein function or detrimental effects on the host cell, the former is inherited in a recessive manner where the latter are dominantly inherited. However, the mechanisms of protein aggregation, disaggregation and degradation in the ER are not well understood. Here we provide an overview of factors that cause protein aggregation in the ER and how the ER handles aggregated proteins. Protein aggregation in the ER can result from intrinsic properties of the protein (hydrophobic residues in the ER), oxidative stress or nutrient depletion. The ER has quality control mechanisms [chaperone functions, ER-associated protein degradation (ERAD) and autophagy] to ensure only correctly folded proteins exit the ER and enter the cis-Golgi compartment. Perturbation of protein folding in the ER activates the unfolded protein response (UPR) that evolved to increase ER protein folding capacity and efficiency and degrade misfolded proteins. Accumulation of misfolded proteins in the ER to a level that exceeds the ER-chaperone folding capacity is a major factor that exacerbates protein aggregation. The most significant ER resident protein that prevents protein aggregation in the ER is the heat shock protein 70 (HSP70) homologue, BiP/GRP78, which is a peptide-dependent ATPase that binds unfolded/misfolded proteins and releases them upon ATP binding. Since exogenous factors can also reduce protein misfolding and aggregation in the ER, such as chemical chaperones and antioxidants, these treatments have potential therapeutic benefit for ER protein aggregation-associated diseases.

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References

  • Allen JR, Nguyen LX, Sargent KE, Lipson KL, Hackett A, Urano F (2004) High ER stress in beta-cells stimulates intracellular degradation of misfolded insulin. Biochem Biophys Res Commun 324:166–170

    Article  CAS  PubMed  Google Scholar 

  • Andersen E, Chollet ME, Baroni M, Pinotti M, Bernardi F, Skarpen E, Sandset PM, Skretting G (2019) The effect of the chemical chaperone 4-phenylbutyrate on secretion and activity of the p.Q160R missense variant of coagulation factor FVII. Cell Biosci 9:69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Anzueto A (2015) Alpha-1 antitrypsin deficiency-associated chronic obstructive pulmonary disease: a family perspective. COPD 12:462–467

    Article  PubMed  Google Scholar 

  • Araki K, Nagata K (2011) Protein folding and quality control in the ER. Cold Spring Harb Perspect Biol 3:a007526

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arunagiri A, Haataja L, Cunningham CN, Shrestha N, Tsai B, Qi L, Liu M, Arvan P (2018) Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes. Ann N Y Acad Sci 1418:5–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arunagiri A, Haataja L, Pottekat A, Pamenan F, Kim S, Zeltser LM, Paton AW, Paton JC, Tsai B, Itkin-Ansari P, Kaufman RJ, Liu M, Arvan P (2019) Proinsulin misfolding is an early event in the progression to type 2 diabetes. elife 8:e44532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Athanasiou D, Kosmaoglou M, Kanuga N, Novoselov SS, Paton AW, Paton JC, Chapple JP, Cheetham ME (2012) BiP prevents rod opsin aggregation. Mol Biol Cell 23:3522–3531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Back SH, Kaufman RJ (2012) Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem 81:767–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Back SH, Lee K, Vink E, Kaufman RJ (2006) Cytoplasmic IRE1alpha-mediated XBP1 mRNA splicing in the absence of nuclear processing and endoplasmic reticulum stress. J Biol Chem 281:18691–18706

    Article  CAS  PubMed  Google Scholar 

  • Bartoszewski R, Rab A, Twitty G, Stevenson L, Fortenberry J, Piotrowski A, Dumanski J, Bebok Z (2008) The mechanism of cystic fibrosis transmembrane conductance regulator transcriptional repression during the unfolded protein response. J Biol Chem 283:12154–12165

    Article  CAS  PubMed  Google Scholar 

  • Behnke J, Mann MJ, Scruggs FL, Feige MJ, Hendershot LM (2016) Members of the Hsp70 family recognize distinct types of sequences to execute ER quality control. Mol Cell 63:739–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blackwood EA, Azizi K, Thuerauf DJ, Paxman RJ, Plate L, Kelly JW, Wiseman RL, Glembotski CC (2019) Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis. Nat Commun 10:187

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bobadilla JL, Macek M Jr, Fine JP, Farrell PM (2002) Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening. Hum Mutat 19:575–606

    Article  CAS  PubMed  Google Scholar 

  • Burrows JAJ, Willis LK, Perlmutter DH (2000) Chemical chaperones mediate increased secretion of mutant α1-antitrypsin (α1-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in α1-AT deficiency. Proc Natl Acad Sci 97:1796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carrell RW, Lomas DA (1997) Conformational disease. Lancet 350:134–138

    Article  CAS  PubMed  Google Scholar 

  • Chandra D, Choy G, Deng X, Bhatia B, Daniel P, Tang DG (2004) Association of active caspase 8 with the mitochondrial membrane during apoptosis: potential roles in cleaving BAP31 and caspase 3 and mediating mitochondrion-endoplasmic reticulum cross talk in etoposide-induced cell death. Mol Cell Biol 24:6592–6607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang S-G, Choi K-D, Jang S-H, Shin H-C (2004) Role of disulfide bonds in the structure and activity of human insulin. Mol Cells 16:323–330

    Google Scholar 

  • Chiang W-C, Hiramatsu N, Messah C, Kroeger H, Lin JH (2012) Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulation. Invest Ophthalmol Vis Sci 53:7159–7166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clark VC, Marek G, Liu C, Collinsworth A, Shuster J, Kurtz T, Nolte J, Brantly M (2018) Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. J Hepatol 69:1357–1364

    Article  CAS  PubMed  Google Scholar 

  • Clerico EM, Tilitsky JM, Meng W, Gierasch LM (2015) How Hsp70 molecular machines interact with their substrates to mediate diverse physiological functions. J Mol Biol 427:1575–1588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clerico EM, Meng W, Pozhidaeva A, Bhasne K, Petridis C, Gierasch LM (2019) Hsp70 molecular chaperones: multifunctional allosteric holding and unfolding machines. Biochem J 476:1653–1677

    Article  CAS  PubMed  Google Scholar 

  • Cooley CB, Ryno LM, Plate L, Morgan GJ, Hulleman JD, Kelly JW, Wiseman RL (2014) Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain. Proc Natl Acad Sci U S A 111:13046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cunningham CN, He K, Arunagiri A, Paton AW, Paton JC, Arvan P, Tsai B (2017) Chaperone-driven degradation of a misfolded proinsulin mutant in parallel with restoration of wild-type insulin secretion. Diabetes 66:741–753

    Article  CAS  PubMed  Google Scholar 

  • Cunningham CN, Williams JM, Knupp J, Arunagiri A, Arvan P, Tsai B (2019) Cells deploy a two-pronged strategy to rectify misfolded proinsulin aggregates. Mol Cell 75:442–456.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du K, Lukacs GL (2009) Cooperative assembly and misfolding of CFTR domains in vivo. Mol Biol Cell 20:1903–1915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du K, Sharma M, Lukacs GL (2005) The DeltaF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR. Nat Struct Mol Biol 12:17–25

    Article  CAS  PubMed  Google Scholar 

  • Easton DP, Kaneko Y, Subjeck JR (2000) The hsp110 and Grp1 70 stress proteins: newly recognized relatives of the Hsp70s. Cell Stress Chaperones 5:276–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eferl R, Ricci R, Kenner L, Zenz R, David J-P, Rath M, Wagner EF (2003) Liver tumor development: c-Jun antagonizes the proapoptotic activity of p53. Cell 112:181–192

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Escamilla AM, Rousseau F, Schymkowitz J, Serrano L (2004) Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat Biotechnol 22:1302–1306

    Article  CAS  PubMed  Google Scholar 

  • Ferris SP, Jaber NS, Molinari M, Arvan P, Kaufman RJ (2013) UDP-glucose:glycoprotein glucosyltransferase (UGGT1) promotes substrate solubility in the endoplasmic reticulum. Mol Biol Cell 24:2597–2608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fritz JM, Dong M, Apsley KS, Martin EP, Na C-L, Sitaraman S, Weaver TE (2013) Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects. Mol Biol Cell 25:431–440

    Article  PubMed  Google Scholar 

  • Ghosh D, Singh PK, Sahay S, Jha NN, Jacob RS, Sen S, Kumar A, Riek R, Maji SK (2015) Structure based aggregation studies reveal the presence of helix-rich intermediate during α-Synuclein aggregation. Sci Rep 5:9228–9228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorasia DG, Dudek NL, Safavi-Hemami H, Perez RA, Schittenhelm RB, Saunders PM, Wee S, Mangum JE, Hubbard MJ, Purcell AW (2016) A prominent role of PDIA6 in processing of misfolded proinsulin. Biochim Biophys Acta (BBA) Proteins Proteom 1864:715–723

    Article  CAS  Google Scholar 

  • GÖrlach A, Bertram K, Hudecova S, Krizanova O (2015) Calcium and ROS: a mutual interplay. Redox Biol 6:260–271

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guinea-Viniegra J, Zenz R, Scheuch H, Hnisz D, Holcmann M, Bakiri L, Schonthaler HB, Sibilia M, Wagner EF (2009) TNFα shedding and epidermal inflammation are controlled by Jun proteins. Genes Dev 23:2663–2674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haataja L, Manickam N, Soliman A, Tsai B, Liu M, Arvan P (2016) Disulfide mispairing during proinsulin folding in the endoplasmic reticulum. Diabetes 65:1050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamdan N, Kritsiligkou P, Grant CM (2017) ER stress causes widespread protein aggregation and prion formation. J Cell Biol 216:2295–2304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han D, Lerner AG, Vande Walle L, Upton J-P, Xu W, Hagen A, Backes BJ, Oakes SA, Papa FR (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138:562–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han J, Song B, Kim J, Kodali VK, Pottekat A, Wang M, Hassler J, Wang S, Pennathur S, Back SH, Katze MG, Kaufman RJ (2015) Antioxidants complement the requirement for protein chaperone function to maintain β-cell function and glucose homeostasis. Diabetes 64:2892–2904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163

    Article  CAS  PubMed  Google Scholar 

  • Hartley T, Siva M, Lai E, Teodoro T, Zhang L, Volchuk A (2010) Endoplasmic reticulum stress response in an INS-1 pancreatic beta-cell line with inducible expression of a folding-deficient proinsulin. BMC Cell Biol 11:59

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hassler JR, Scheuner DL, Wang S, Han J, Kodali VK, Li P, Nguyen J, George JS, Davis C, Wu SP, Bai Y, Sartor M, Cavalcoli J, Malhi H, Baudouin G, Zhang Y, Yates JR III, Itkin-Ansari P, Volkmann N, Kaufman RJ (2015) The IRE1alpha/XBP1s pathway is essential for the glucose response and protection of beta cells. PLoS Biol 13:e1002277

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hetz C, Glimcher LH (2009) Fine-tuning of the unfolded protein response: assembling the IRE1alpha interactome. Mol Cell 35:551–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hidvegi T, Schmidt B, Hale P, Perlmutter D (2005) Accumulation of mutant 1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NF B, and BAP31 but not the unfolded protein response. J Biol Chem 280:39002–39015

    Article  CAS  PubMed  Google Scholar 

  • Hollien J, Weissman JS (2006) Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313:104–107

    Article  CAS  PubMed  Google Scholar 

  • Hong DP, Ahmad A, Fink AL (2006) Fibrillation of human insulin A and B chains. Biochemistry 45:9342–9353

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Gao Y, Zhang M, Deng K-Y, Singh R, Tian Q, Gong Y, Pan Z, Liu Q, Boisclair YR, Long Q (2019) Endoplasmic reticulum–associated degradation (ERAD) has a critical role in supporting glucose-stimulated insulin secretion in pancreatic β-cells. Diabetes 68:733

    Article  CAS  PubMed  Google Scholar 

  • Hui L, Zatloukal K, Scheuch H, Stepniak E, Wagner EF (2008) Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest 118:3943–3953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hunt JF, Wang C, Ford RC (2013) Cystic fibrosis transmembrane conductance regulator (ABCC7) structure. Cold Spring Harb Perspect Med 3:a009514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hwang J, Qi L (2018) Quality control in the endoplasmic reticulum: crosstalk between ERAD and UPR pathways. Trends Biochem Sci 43:593–605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iadanza MG, Jackson MP, Hewitt EW, Ranson NA, Radford SE (2018) A new era for understanding amyloid structures and disease. Nat Rev Mol Cell Biol 19:755–773

    Article  CAS  PubMed  Google Scholar 

  • Iannuzzi C, Borriello M, Portaccio M, Irace G, Sirangelo I (2017) Insights into insulin fibril assembly at physiological and acidic pH and related amyloid intrinsic fluorescence. Int J Mol Sci 18:2551

    Article  PubMed Central  CAS  Google Scholar 

  • Iljina M, Garcia GA, Horrocks MH, Tosatto L, Choi ML, Ganzinger KA, Abramov AY, Gandhi S, Wood NW, Cremades N, Dobson CM, Knowles TPJ, Klenerman D (2016) Kinetic model of the aggregation of alpha-synuclein provides insights into prion-like spreading. Proc Natl Acad Sci 113:E1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inden M, Kitamura Y, Takeuchi H, Yanagida T, Takata K, Kobayashi Y, Taniguchi T, Yoshimoto K, Kaneko M, Okuma Y, Taira T, Ariga H, Shimohama S (2007) Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone. J Neurochem 101:1491–1504

    Article  CAS  PubMed  Google Scholar 

  • Itoh N, Okamoto H (1980) Translational control of proinsulin synthesis by glucose. Nature 283:100–102

    Article  CAS  PubMed  Google Scholar 

  • Ivanova MI, Sievers SA, Sawaya MR, Wall JS, Eisenberg D (2009) Molecular basis for insulin fibril assembly. Proc Natl Acad Sci U S A 106:18990–18995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Izumi T, Yokota-Hashimoto H, Zhao S, Wang J, Halban PA, Takeuchi T (2003) Dominant negative pathogenesis by mutant proinsulin in the akita diabetic mouse. Diabetes 52:409

    Article  CAS  PubMed  Google Scholar 

  • Jang I, Pottekat A, Poothong J, Yong J, Lagunas-Acosta J, Charbono A, Chen Z, Scheuner DL, Liu M, Itkin-Ansari P, Arvan P, Kaufman RJ (2019) PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity. elife 8:e44528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiménez JL, Nettleton EJ, Bouchard M, Robinson CV, Dobson CM, Saibil HR (2002) The protofilament structure of insulin amyloid fibrils. Proc Natl Acad Sci U S A 99:9196

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jin JK, Blackwood EA, Azizi K, Thuerauf DJ, Fahem AG, Hofmann C, Kaufman RJ, Doroudgar S, Glembotski CC (2017) ATF6 decreases myocardial ischemia/reperfusion damage and links ER stress and oxidative stress signaling pathways in the heart. Circ Res 120:862–875

    Article  CAS  PubMed  Google Scholar 

  • Kalsheker N, Morley S, Morgan K (2002) Gene regulation of the serine proteinase inhibitors alpha(1)-antitrypsin and alpha(1)-antichymotrypsin. Biochem Soc Trans 30(2):93–98

    Article  CAS  PubMed  Google Scholar 

  • Kang J, Lim L, Song J (2019) ATP binds and inhibits the neurodegeneration-associated fibrillization of the FUS RRM domain. Commun Biol 2:223

    Article  PubMed  PubMed Central  Google Scholar 

  • Kania E, PajĄK B, Orzechowski A (2015) Calcium homeostasis and ER stress in control of autophagy in cancer cells. Biomed Res Int 2015:352794

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kerbiriou M, Le Drévo MA, FÉrec C, Trouvé P (2007) Coupling cystic fibrosis to endoplasmic reticulum stress: differential role of Grp78 and ATF6. Biochim Biophys Acta 1772:1236–1249

    Article  CAS  PubMed  Google Scholar 

  • Khurana R, Ionescu-Zanetti C, Pope M, Li J, Nielson L, Ramírez-Alvarado M, Regan L, Fink AL, Carter SA (2003) A general model for amyloid fibril assembly based on morphological studies using atomic force microscopy. Biophys J 85:1135–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SJ, Skach WR (2012) Mechanisms of CFTR folding at the endoplasmic reticulum. Front Pharmacol 3:201

    CAS  PubMed  PubMed Central  Google Scholar 

  • Knorre A, Wagner M, Schaefer HE, Colledge WH, Pahl HL (2002) DeltaF508-CFTR causes constitutive NF-kappaB activation through an ER-overload response in cystic fibrosis lungs. Biol Chem 383:271–282

    Article  CAS  PubMed  Google Scholar 

  • Kusum Y, Anurag Y, Priyanka V, Veda PP, Upendra ND (2019) Protein misfolding diseases and therapeutic approaches. Curr Protein Pept Sci 20:1226–1245

    Article  CAS  Google Scholar 

  • Lange AM, Altynova ES, Nguyen GN, Sabatino DE (2016) Overexpression of factor VIII after AAV delivery is transiently associated with cellular stress in hemophilia A mice. Mol Ther Methods Clin Dev 3:16064

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50:752–763

    Article  CAS  PubMed  Google Scholar 

  • Lindblad D, Blomenkamp K, Teckman J (2007) Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. Hepatology 46:1228–1235

    Article  CAS  PubMed  Google Scholar 

  • Liu M, Hodish I, Haataja L, Lara-Lemus R, Rajpal G, Wright J, Arvan P (2010) Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth. Trends Endocrinol Metab 21:652–659

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu M, Sun J, Cui J, Chen W, Guo H, Barbetti F, Arvan P (2015) INS-gene mutations: from genetics and beta cell biology to clinical disease. Mol Asp Med 42:3–18

    Article  CAS  Google Scholar 

  • Lomas DA, Li-Evans D, Finch JT, Carrell RW (1992) The mechanism of Z α1-antitrypsin accumulation in the liver. Nature 357:605–607

    Article  CAS  PubMed  Google Scholar 

  • Lu Y, Xiong X, Helm A, Kimani K, Bragin A, Skach WR (1998) Co- and posttranslational translocation mechanisms direct cystic fibrosis transmembrane conductance regulator N terminus transmembrane assembly. J Biol Chem 273:568–576

    Article  CAS  PubMed  Google Scholar 

  • Malhotra JD, Miao H, Zhang K, Wolfson A, Pennathur S, Pipe SW, Kaufman RJ (2008) Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc Natl Acad Sci U S A 105:18525–18530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mann KG (1999) Biochemistry and physiology of blood coagulation. Thromb Haemost 82:165–174

    Article  CAS  PubMed  Google Scholar 

  • Marquette KA, Pittman DD, Kaufman RJ (1995) A 110-amino acid region within the A1-domain of coagulation factor VIII inhibits secretion from mammalian cells. J Biol Chem 270:10297–10303

    Article  CAS  PubMed  Google Scholar 

  • Meisl G, Yang X, Frohm B, Knowles TP, Linse S (2016) Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Abeta-peptide. Sci Rep 6:18728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muzaffar M, Ahmad A (2011) The mechanism of enhanced insulin amyloid fibril formation by NaCl is better explained by a conformational change model. PLoS One 6:e27906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oliver JD, Van Der Wal FJ, Bulleid NJ, High S (1997) Interaction of the thiol-dependent reductase ERp57 with nascent glycoproteins. Science 275:86–88

    Article  CAS  PubMed  Google Scholar 

  • Orlova NA, Kovnir SV, Vorobiev II, Gabibov AG, Vorobiev AI (2013) Blood clotting factor VIII: from evolution to therapy. Acta Nat 5:19–39

    Article  CAS  Google Scholar 

  • Ostedgaard LS, Rich DP, Deberg LG, Welsh MJ (1997) Association of domains within the cystic fibrosis transmembrane conductance regulator. Biochemistry 36:1287–1294

    Article  CAS  PubMed  Google Scholar 

  • Özcan U, Yilmaz E, Özcan L, Furuhashi M, Vaillancourt E, Smith RO, GÖrgün CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson T, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Dickson SP, Ellison N, Hall M, Hendrix K, Kittle G, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME (2020) Trial of sodium phenylbutyrate–taurursodiol for amyotrophic lateral sclerosis. N Engl J Med 383:919–930

    Article  CAS  PubMed  Google Scholar 

  • Parodi AJ, Behrens NH, Leloir LF, Carminatti H (1972) The role of polyprenol-bound saccharides as intermediates in glycoprotein synthesis in liver. Proc Natl Acad Sci U S A 69:3268–3272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pastore N, Attanasio S, Granese B, Castello R, Teckman J, Wilson AA, Ballabio A, Brunetti-Pierri N (2017) Activation of the c-Jun N-terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1-antitrypsin. Hepatology 65:1865–1874

    Article  CAS  PubMed  Google Scholar 

  • Patel A, Malinovska L, Saha S, Wang J, Alberti S, Krishnan Y, Hyman AA (2017) ATP as a biological hydrotrope. Science 356:753

    Article  CAS  PubMed  Google Scholar 

  • Paton AW, Beddoe T, Thorpe CM, Whisstock JC, Wilce MC, Rossjohn J, Talbot UM, Paton JC (2006) AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature 443:548–552

    Article  CAS  PubMed  Google Scholar 

  • Paxman R, Plate L, Blackwood EA, Glembotski C, Powers ET, Wiseman RL, Kelly JW (2018) Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins. elife 7:e37168

    Article  PubMed  PubMed Central  Google Scholar 

  • Pelletier M, Marcil A, Sevigny G, Jakob CA, Tessier D, Chevet E, Menard R, Bergeron J, Thomas D (2000) The heterodimeric structure of glucosidase II is required for its activity, solubility, and localization in vivo. Glycobiology 10:815–827

    Article  CAS  PubMed  Google Scholar 

  • Perlmutter DH (2002) Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury. J Clin Invest 110:1579–1583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perlmutter DH, Brodsky JL, Balistreri WF, Trapnell BC (2007) Molecular pathogenesis of alpha-1-antitrypsin deficiency-associated liver disease: a meeting review. Hepatology 45:1313–1323

    Article  PubMed  Google Scholar 

  • Plate L, Cooley CB, Chen JJ, Paxman RJ, Gallagher CM, Madoux F, Genereux JC, Dobbs W, Garza D, Spicer TP, Scampavia L, Brown SJ, Rosen H, Powers ET, Walter P, Hodder P, Wiseman RL, Kelly JW (2016) Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. elife 5:e15550

    Article  PubMed  PubMed Central  Google Scholar 

  • Pobre K, Poet G, Hendershot L (2018) The endoplasmic reticulum (ER) chaperone BiP is a master regulator of ER functions: Getting by with a little help from ERdj friends. J Biol Chem 294:2098–2108

    Article  PubMed  PubMed Central  Google Scholar 

  • Poothong J, Sopha P, Kaufman RJ, Tirasophon W (2017) IRE1α nucleotide sequence cleavage specificity in the unfolded protein response. FEBS Lett 591:406–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poothong J, Pottekat A, Siriin M, Campos AR, Paton AW, Paton JC, Lagunas-Acosta J, Chen Z, Swift M, Volkmann N, Hanein D, Yong J, Kaufman RJ (2020) Factor VIII exhibits chaperone-dependent and glucose-regulated reversible amyloid formation in the endoplasmic reticulum. Blood 135(21):1899–1911

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL et al (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073

    Article  CAS  PubMed  Google Scholar 

  • Roth SD, Schüttrumpf J, Milanov P, Abriss D, Ungerer C, Quade-Lyssy P, Simpson JC, Pepperkok R, Seifried E, Tonn T (2012) Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A. PLoS One 7:e44505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruggiano A, Foresti O, Carvalho P (2014) ER-associated degradation: protein quality control and beyond. J Cell Biol 204:869–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rutkowski DT, Kaufman RJ (2007) That which does not kill me makes me stronger: adapting to chronic ER stress. Trends Biochem Sci 32:469–476

    Article  CAS  PubMed  Google Scholar 

  • Rutkowski DT, Arnold SM, Miller CN, Wu J, Li J, Gunnison KM, Mori K, Sadighi Akha AA, Raden D, Kaufman RJ (2006) Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol 4:e374

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schmidt BZ, Perlmutter DH (2005) Grp78, Grp94, and Grp170 interact with α1-antitrypsin mutants that are retained in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 289:G444–G455

    Article  CAS  PubMed  Google Scholar 

  • Schwaller M, Wilkinson B, Gilbert HF (2003) Reduction-reoxidation cycles contribute to catalysis of disulfide isomerization by protein-disulfide isomerase. J Biol Chem 278:7154–7159

    Article  CAS  PubMed  Google Scholar 

  • Segeritz C-P, Rashid ST, De Brito MC, Serra MP, Ordonez A, Morell CM, Kaserman JE, Madrigal P, Hannan NRF, Gatto L, Tan L, Wilson AA, Lilley K, Marciniak SJ, Gooptu B, Lomas DA, Vallier L (2018) hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency. J Hepatol 69: 851–860

    Google Scholar 

  • Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee A-H, Qian S-B, Zhao H, Yu X, Yang L, Tan BK, Rosenwald A, Hurt EM, Petroulakis E, Sonenberg N, Yewdell JW, Calame K, Glimcher LH, Staudt LM (2004) XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21:81–93

    Article  CAS  PubMed  Google Scholar 

  • Shammas SL, Garcia GA, Kumar S, Kjaergaard M, Horrocks MH, Shivji N, Mandelkow E, Knowles TP, Mandelkow E, Klenerman D (2015) A mechanistic model of tau amyloid aggregation based on direct observation of oligomers. Nat Commun 6:7025

    Article  CAS  PubMed  Google Scholar 

  • Sheppard DN, Welsh MJ (1999) Structure and function of the CFTR chloride channel. Physiol Rev 79:S23–S45

    Article  CAS  PubMed  Google Scholar 

  • Shoulders MD, Ryno LM, Genereux JC, Moresco JJ, Tu PG, Wu C, Yates JR III, Su AI, Kelly JW, Wiseman RL (2013) Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 3:1279–1292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sicorello A, Torrassa S, Soldi G, Gianni S, Travaglini-Allocatelli C, Taddei N, Relini A, Chiti F (2009) Agitation and high ionic strength induce amyloidogenesis of a folded PDZ domain in native conditions. Biophys J 96:2289–2298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith SE, Granell S, Salcedo-Sicilia L, Baldini G, Egea G, Teckman JH, Baldini G (2011) Activating transcription factor 6 limits intracellular accumulation of mutant α(1)-antitrypsin Z and mitochondrial damage in hepatoma cells. J Biol Chem 286:41563–41577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song S, Tan J, Miao Y, Zhang Q (2018) Crosstalk of ER stress-mediated autophagy and ER-phagy: involvement of UPR and the core autophagy machinery. J Cell Physiol 233:3867–3874

    Article  CAS  PubMed  Google Scholar 

  • Suaud L, Miller K, Alvey L, Yan W, Robay A, Kebler C, Kreindler JL, Guttentag S, Hubbard MJ, Rubenstein RC (2011) ERp29 regulates DeltaF508 and wild-type cystic fibrosis transmembrane conductance regulator (CFTR) trafficking to the plasma membrane in cystic fibrosis (CF) and non-CF epithelial cells. J Biol Chem 286:21239–21253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun J, Xiong Y, Li X, Haataja L, Chen W, Mir SA, Lv L, Madley R, Larkin D, Anjum A, Dhayalan B, Rege N, Wickramasinghe ND, Weiss MA, Itkin-Ansari P, Kaufman RJ, Ostrov DA, Arvan P, Liu M (2020) Role of proinsulin self-association in mutant INS gene-induced diabetes of youth. Diabetes 69(5):954–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tagliavacca L, Wang Q, Kaufman RJ (2000) ATP-dependent dissociation of non-disulfide-linked aggregates of coagulation factor VIII is a rate-limiting step for secretion. Biochemistry 39:1973–1981

    Article  CAS  PubMed  Google Scholar 

  • Tannous A, Pisoni GB, Hebert DN, Molinari M (2015) N-linked sugar-regulated protein folding and quality control in the ER. Semin Cell Dev Biol 41:79–89

    Article  CAS  PubMed  Google Scholar 

  • Teckman JH, An J-K, Blomenkamp K, Schmidt B, Perlmutter D (2004) Mitochondrial autophagy and injury in the liver in α1-antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol 286:G851–G862

    Article  CAS  PubMed  Google Scholar 

  • Tenidis K, Waldner M, Bernhagen J, Fischle W, Bergmann M, Weber M, Merkle M-L, Voelter W, Brunner H, Kapurniotu A (2000) Identification of a penta- and hexapeptide of islet amyloid polypeptide (IAPP) with amyloidogenic and cytotoxic properties1 1Edited by R. Huber. J Mol Biol 295:1055–1071

    Article  CAS  PubMed  Google Scholar 

  • Teodoro-Morrison T, Schuiki I, Zhang L, Belsham DD, Volchuk A (2013) GRP78 overproduction in pancreatic beta cells protects against high-fat-diet-induced diabetes in mice. Diabetologia 56:1057–1067

    Article  CAS  PubMed  Google Scholar 

  • Tirasophon W, Welihinda AA, Kaufman RJ (1998) A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12:1812–1824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tran DT, Pottekat A, Mir SA, Loguercio S, Jang I, Campos AR, Scully KM, Lahmy R, Liu M, Arvan P, Balch WE, Kaufman RJ, Itkin-Ansari P (2020) Unbiased profiling of the human proinsulin biosynthetic interaction network reveals a role for peroxiredoxin 4 in proinsulin folding. Diabetes 69(8):1723–1734

    Article  PubMed  PubMed Central  Google Scholar 

  • Tsuchiya Y, Saito M, Kadokura H, Miyazaki J-I, Tashiro F, Imagawa Y, Iwawaki T, Kohno K (2018) IRE1–XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells. J Cell Biol 217(4):1287–1301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Upton J-P, Wang L, Han D, Wang E, Huskey N, Lim L, Truitt M, McManus M, Ruggero D, Goga A, Papa F, Oakes S (2012) IRE1α Cleaves Select microRNAs during ER Stress to Derepress Translation of Proapoptotic Caspase-2. Science 338(6108):818–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664

    Article  CAS  PubMed  Google Scholar 

  • Usui M, Yamaguchi S, Tanji Y, Tominaga R, Ishigaki Y, Fukumoto M, Katagiri H, Mori K, Oka Y, Ishihara H (2012) Atf6alpha-null mice are glucose intolerant due to pancreatic beta-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism 61:1118–1128

    Article  CAS  PubMed  Google Scholar 

  • Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA (2011) Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 108:18843–18848

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Varga K, Jurkuvenaite A, Wakefield J, Hong JS, Guimbellot JS, Venglarik CJ, Niraj A, Mazur M, Sorscher EJ, Collawn JF, Bebök Z (2004) Efficient intracellular processing of the endogenous cystic fibrosis transmembrane conductance regulator in epithelial cell lines. J Biol Chem 279:22578–22584

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Takeuchi T, Tanaka S, Kubo SK, Kayo T, Lu D, Takata K, Koizumi A, Izumi T (1999) A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. J Clin Invest 103:27–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang A, Al-Kuhlani M, Johnston SC, Ojcius DM, Chou J, Dean D (2013) Transcription factor complex AP-1 mediates inflammation initiated by Chlamydia pneumoniae infection. Cell Microbiol 15:779–794

    Article  CAS  PubMed  Google Scholar 

  • Wright JM, Zeitlin PL, Cebotaru L, Guggino SE, Guggino WB (2004) Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics 16:204–211

    Article  CAS  PubMed  Google Scholar 

  • Yadav K, Yadav A, Vashistha P, Pandey VP, Dwivedi UN (2019) Protein misfolding diseases and therapeutic approaches. Curr Protein Pept Sci 20:1226–1245

    Article  CAS  PubMed  Google Scholar 

  • Yong J, Bischof H, Burgstaller S, Siirin M, Murphy A, Malli R, Kaufman RJ (2019) Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca(2). elife 8:e49682

    Article  PubMed  PubMed Central  Google Scholar 

  • Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Lai E, Teodoro T, Volchuk A (2009) GRP78, but not protein-disulfide isomerase, partially reverses hyperglycemia-induced inhibition of insulin synthesis and secretion in pancreatic-cells. J Biol Chem 284:5289–5298

    Article  CAS  PubMed  Google Scholar 

  • Zhou W, Bercury K, Cummiskey J, Luong N, Lebin J, Freed CR (2011) Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem 286:14941–14951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zolotukhin I, Markusic DM, Palaschak B, Hoffman BE, Srikanthan MA, Herzog RW (2016) Potential for cellular stress response to hepatic factor VIII expression from AAV vector. Mol Ther Methods Clin Dev 3:16063

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH/NCI grants CA198103, DK103185, DK110973, DK113171, AG062190 to RJK and the Sanford Burnham Prebys NCI Cancer Center Grant P30 CA030199.

Funding

NIH/NCI Grants R01CA198103, R01DK113171, R01DK103185, R24DK110973, R01AG062190 and the Sanford Burnham Prebys NCI Cancer Center Grant P30 CA030199.

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  1. Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    Juthakorn Poothong, Insook Jang & Randal J. Kaufman

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  1. Juthakorn Poothong
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  2. Insook Jang
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  3. Randal J. Kaufman
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Correspondence to Randal J. Kaufman .

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  1. School of Human Nutrition, McGill University, Ste. Anne de Bellevue, QC, Canada

    Luis B. Agellon

  2. Department of Biochemistry, University of Alberta, Edmonton, AB, Canada

    Marek Michalak

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Poothong, J., Jang, I., Kaufman, R.J. (2021). Defects in Protein Folding and/or Quality Control Cause Protein Aggregation in the Endoplasmic Reticulum. In: Agellon, L.B., Michalak, M. (eds) Cellular Biology of the Endoplasmic Reticulum . Progress in Molecular and Subcellular Biology, vol 59. Springer, Cham. https://doi.org/10.1007/978-3-030-67696-4_6

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