Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis.
diabetes
disulfide bonds
pancreatic islets
proinsulin trafficking
β‐cells
Journal
Protein science : a publication of the Protein Society
ISSN: 1469-896X
Titre abrégé: Protein Sci
Pays: United States
ID NLM: 9211750
Informations de publication
Date de publication:
Apr 2024
Apr 2024
Historique:
revised:
23
01
2024
received:
13
11
2023
accepted:
14
02
2024
medline:
21
3
2024
pubmed:
21
3
2024
entrez:
21
3
2024
Statut:
ppublish
Résumé
Primary defects in folding of mutant proinsulin can cause dominant-negative proinsulin accumulation in the endoplasmic reticulum (ER), impaired anterograde proinsulin trafficking, perturbed ER homeostasis, diminished insulin production, and β-cell dysfunction. Conversely, if primary impairment of ER-to-Golgi trafficking (which also perturbs ER homeostasis) drives misfolding of nonmutant proinsulin-this might suggest bi-directional entry into a common pathological phenotype (proinsulin misfolding, perturbed ER homeostasis, and deficient ER export of proinsulin) that can culminate in diminished insulin storage and diabetes. Here, we've challenged β-cells with conditions that impair ER-to-Golgi trafficking, and devised an accurate means to assess the relative abundance of distinct folded/misfolded forms of proinsulin using a novel nonreducing SDS-PAGE/immunoblotting protocol. We confirm abundant proinsulin misfolding upon introduction of a diabetogenic INS mutation, or in the islets of db/db mice. Whereas blockade of proinsulin trafficking in Golgi/post-Golgi compartments results in intracellular accumulation of properly-folded proinsulin (bearing native disulfide bonds), impairment of ER-to-Golgi trafficking (regardless whether such impairment is achieved by genetic or pharmacologic means) results in decreased native proinsulin with more misfolded proinsulin. Remarkably, reversible ER-to-Golgi transport defects (such as treatment with brefeldin A or cellular energy depletion) upon reversal quickly restore the ER folding environment, resulting in the disappearance of pre-existing misfolded proinsulin while preserving proinsulin bearing native disulfide bonds. Thus, proper homeostatic balance of ER-to-Golgi trafficking is linked to a more favorable proinsulin folding (as well as trafficking) outcome.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e4949Subventions
Organisme : National Institute of Diabetes and Digestive and Kidney Diseases, NIH
ID : R01-DK48280
Organisme : National Institute of Diabetes and Digestive and Kidney Diseases, NIH
ID : U01-DK127747
Organisme : National Institute of Diabetes and Digestive and Kidney Diseases, NIH
ID : R01-DK132689
Organisme : JDRF
ID : 3-SR2022-1203-S-B
Pays : United States
Organisme : National Natural Science Foundation of China
ID : 82220108014
Organisme : National Natural Science Foundation of China
ID : 81830025
Organisme : National Key R&D Program
ID : 2019YFA0802502
Organisme : National Key R&D Program
ID : 2022YFE0131400
Organisme : Innovative Medicines Initiative
ID : 115797
Organisme : Innovative Medicines Initiative
ID : 945268
Organisme : Union's Horizon 2020 Research and Innovation Programme
Organisme : Helmsley Charitable Trust
Organisme : Francophone Foundation for Diabetes Research
Organisme : French Diabetes Federation
Organisme : Abbott
Organisme : Eli Lilly
Organisme : Merck Sharp & Dohme
Organisme : Novo Nordisk
Organisme : Fonds National de la Recherche Scientifique
Organisme : Walloon Region SPW-EER Win2Wal
Organisme : Pandarome Project
ID : 40007487
Organisme : FWO
Organisme : F.R.S.-FNRS
Organisme : Fund for Research Training in Industry and Agriculture - FNRS
Informations de copyright
© 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.
Références
Adams BM, Oster ME, Hebert DN. Protein quality control in the endoplasmic reticulum. Protein J. 2019;38:317–329.
Alam M, Arunagiri A, Haataja L, Torres M, Larkin D, Kappler J, et al. Predisposition to proinsulin misfolding as a genetic risk to diet‐induced diabetes. Diabetes. 2021;70:2580–2594.
Alarcon C, Boland BB, Uchizono Y, Moore PC, Peterson B, Rajan S, et al. Pancreatic beta‐cell adaptive plasticity in obesity increases insulin production but adversely affects secretory function. Diabetes. 2016;65:438–450.
Arunagiri A, Haataja L, Cunningham CN, Shrestha N, Tsai B, Qi L, et al. Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes. Ann N Y Acad Sci. 2018;1418:5–19.
Arunagiri A, Haataja L, Pottekat A, Pamenan F, Kim S, Zeltser LM, et al. Proinsulin misfolding is an early event in the progression to type 2 diabetes. eLife. 2019;8:e44532.
Back SH, Kaufman RJ. Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem. 2012;81:767–793.
Chen LM, Yang XW, Tang JG. Acidic residues on the N‐terminus of proinsulin C‐peptide are important for the folding of insulin precursor. J Biochem. 2002;131:855–859.
Colanzi A, Grimaldi G, Catara G, Valente C, Cericola C, Liberali P, et al. Molecular mechanism and functional role of brefeldin A‐mediated ADP‐ribosylation of CtBP1/BARS. Proc Natl Acad Sci USA. 2013;110:9794–9799.
De Franco E, Lytrivi M, Ibrahim H, Montaser H, Wakeling MN, Fantuzzi F, et al. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress. J Clin Invest. 2020;130:6338–6353.
Dodson G, Steiner D. The role of assembly in insulin's biosynthesis. Curr Opin Struct Biol. 1998;8:189–194.
Dornbos P, Koesterer R, Ruttenburg A, Nguyen T, Cole JB, Consortium A‐TDG, et al. A combined polygenic score of 21,293 rare and 22 common variants improves diabetes diagnosis based on hemoglobin A1C levels. Nat Genet. 2022;54:1609–1614.
Ellgaard L, Helenius A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol. 2003;4:181–191.
Fang J, Liu M, Zhang X, Sakamoto T, Taatjes DJ, Jena BP, et al. COPII‐dependent ER export: a critical component of insulin biogenesis and beta‐cell ER homeostasis. Mol Endocrinol. 2015;29:1156–1169.
Gupta S, McGrath B, Cavener DR. PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes. 2010;59:1937–1947.
Haataja L, Arunagiri A, Hassan A, Regan K, Tsai B, Dhayalan B, et al. Distinct states of proinsulin misfolding in MIDY. Cell Mol Life Sci. 2021;78:6017–6031.
Haataja L, Manickam N, Soliman A, Tsai B, Liu M, Arvan P. Disulfide mispairing during proinsulin folding in the endoplasmic reticulum. Diabetes. 2016;65:1050–1060.
Harding HP, Zyryanova AF, Ron D. Uncoupling proteostasis and development in vitro with a small molecule inhibitor of the pancreatic endoplasmic reticulum kinase, PERK. J Biol Chem. 2012;287:44338–44344.
Henriksson M, Nordling E, Melles E, Shafqat J, Stahlberg M, Ekberg K, et al. Separate functional features of proinsulin C‐peptide. Cell Mol Life Sci. 2005;62:1772–1778.
Hoefner C, Bryde TH, Pihl C, Tiedemann SN, Bresson SE, Hotiana HA, et al. FK506‐binding protein 2 participates in proinsulin folding. Biomolecules. 2023;13(1):152.
Huang XF, Arvan P. Intracellular transport of proinsulin in pancreatic B‐cells: structural maturation probed by disulfide accessibility. J Biol Chem. 1995;270:20417–20423.
Jamieson JD, Palade GE. Intracellular transport of secretory proteins in the pancreatic exocrine cell. IV. Metabolic requirements. J Cell Biol. 1968;39:589–603.
Jang I, Pottekat A, Poothong J, Yong J, Lagunas‐Acosta J, Charbono A, et al. PDIA1/P4HB is required for efficient proinsulin maturation and beta cell health in response to diet induced obesity. Elife. 2019;8:e44528.
Kumari D, Brodsky JL. The targeting of native proteins to the endoplasmic reticulum‐associated degradation (ERAD) pathway: an expanding repertoire of regulated substrates. Biomolecules. 2021;11(8):1185.
Landreh M, Johansson J, Wahren J, Jornvall H. The structure, molecular interactions and bioactivities of proinsulin C‐peptide correlate with a tripartite molecule. Biomol Concepts. 2014;5:109–118.
Lind J, Lindahl E, Peralvarez‐Marin A, Holmlund A, Jornvall H, Maler L. Structural features of proinsulin C‐peptide oligomeric and amyloid states. FEBS J. 2010;277:3759–3768.
Liu M, Hodish I, Haataja L, Lara‐Lemus AR, Rajpal G, Wright J, et al. Proinsulin misfolding and diabetes: mutant INS gene‐induced diabetes of youth. Trends Endocrinol Metab. 2010;21:652–659.
Liu M, Huang Y, Xu X, Li X, Maroof A, Arunagiri A, et al. Normal and defective pathways in biogenesis and maintenance of the insulin storage pool. J Clin Invest. 2021;131:e142240.
Liu M, Weiss MA, Arunagiri A, Yong J, Rege N, Sun J, et al. Biosynthesis, structure, and folding of the insulin precursor protein. Diabetes Obes Metab. 2018;20:28–50.
Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, et al. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia. 2007;50:2486–2494.
Matlin KS, Simons K. Reduced temperature prevents transfer of a membrane glycoprotein to the cell surface but does not prevent terminal glycosylation. Cell. 1983;34:233–243.
Min CY, Qiao ZS, Feng YM. Unfolding of human proinsulin. Intermediates and possible role of its C‐peptide in folding/unfolding. Eur J Biochem. 2004;271:1737–1747.
Ninagawa S, Tada S, Okumura M, Inoguchi K, Kinoshita M, Kanemura S, et al. Antipsychotic olanzapine‐induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes. Elife. 2020;9:e60970.
Poothong J, Jang I, Kaufman RJ. Defects in protein folding and/or quality control cause protein aggregation in the endoplasmic reticulum. Prog Mol Subcell Biol. 2021;59:115–143.
Preston AM, Gurisik E, Bartley C, Laybutt DR, Biden TJ. Reduced endoplasmic reticulum (ER)‐to‐Golgi protein trafficking contributes to ER stress in lipotoxic mouse beta cells by promoting protein overload. Diabetologia. 2009;52:2369–2373.
Rajpal G, Schuiki I, Liu M, Volchuk A, Arvan P. Action of protein disulfide isomerase on proinsulin exit from endoplasmic reticulum of pancreatic beta‐cells. J Biol Chem. 2012;287:43–47.
Renstrom E, Eliasson L, Bokvist K, Rorsman P. Cooling inhibits exocytosis in single mouse pancreatic B‐cells by suppression of granule mobilization. J Physiol. 1996;494:41–52.
Rohli KE, Boyer CK, Bearrows SC, Moyer MR, Elison WS, Bauchle CJ, et al. ER redox homeostasis regulates proinsulin trafficking and insulin granule formation in the pancreatic islet beta‐cell. Function (Oxf). 2022;3:zqac051.
Saegusa K, Matsunaga K, Maeda M, Saito K, Izumi T, Sato K. Cargo receptor Surf4 regulates endoplasmic reticulum export of proinsulin in pancreatic beta‐cells. Commun Biol. 2022;5:458.
Shrestha N, De Franco E, Arvan P, Cnop M. Pathological beta‐cell endoplasmic reticulum stress in type 2 diabetes: current evidence. Front Endocrinol (Lausanne). 2021;12:650158.
Sowers CR, Wang R, Bourne RA, McGrath BC, Hu J, Bevilacqua SC, et al. The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones. J Biol Chem. 2018;293:5134–5149.
Sun J, Xiong Y, Li X, Haataja L, Chen W, Mir SA, et al. Role of proinsulin self‐association in mutant INS gene‐induced diabetes of youth. Diabetes. 2020;69:954–964.
Tartakoff AM. Perturbation of vesicular traffic with the carboxylic ionophore monensin. Cell. 1983;32:1026–1028.
Tran DT, Pottekat A, Mir SA, Loguercio S, Jang I, Campos AR, et al. Unbiased profiling of the human proinsulin biosynthetic interaction network reveals a role for peroxiredoxin 4 in proinsulin folding. Diabetes. 2020;69:1723–1734.
Vinuela A, Varshney A, van de Bunt M, Prasad RB, Asplund O, Bennett A, et al. Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D. Nat Commun. 2020;11:4912.
Wang S, Wei W, Zheng Y, Hou J, Dou Y, Zhang S, et al. The role of insulin C‐peptide in the coevolution analyses of the insulin signaling pathway: a hint for its functions. PloS One. 2012;7:e52847.
Wright J, Birk J, Haataja L, Liu M, Ramming T, Weiss MA, et al. Endoplasmic reticulum oxidoreductin‐1alpha (Ero1alpha) improves folding and secretion of mutant proinsulin and limits mutant proinsulin‐induced endoplasmic reticulum stress. J Biol Chem. 2013;288:31010–31018.
Yang J, Zhen J, Feng W, Fan Z, Ding L, Yang X, et al. IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of beta cells. Proc Natl Acad Sci USA. 2022;119:e2204443119.
Yang Y, Hua QX, Liu J, Shimizu EH, Choquette MH, Mackin RB, et al. Solution structure of proinsulin: connecting domain flexibility and prohormone processing. J Biol Chem. 2010;285:7847–7851.
Yong J, Johnson JD, Arvan P, Han J, Kaufman RJ. Therapeutic opportunities for pancreatic beta‐cell ER stress in diabetes mellitus. Nat Rev Endocrinol. 2021;17:455–467.
Yuan Q, Tang W, Zhang X, Hinson JA, Liu C, Osei K, et al. Proinsulin atypical maturation and disposal induces extensive defects in mouse Ins2+/Akita beta‐cells. PloS One. 2012;7:e35098.
Zhu R, Li X, Xu J, Barrabi C, Kekulandara D, Woods J, et al. Defective endoplasmic reticulum export causes proinsulin misfolding in pancreatic beta cells. Mol Cell Endocrinol. 2019;493:110470.