IRE1–XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells

Tsuchiya, Yosuke; Saito, Michiko; Kadokura, Hiroshi; Miyazaki, Jun‐ichi; Tashiro, Fumi; Imagawa, Yusuke; Iwawaki, Takao; Kohno, Kenji

doi:10.1083/jcb.201707143

Cited by 88 publications

(60 citation statements)

References 53 publications

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“…Increasing evidence indicates that proinsulin misfolding and ER stress not only are the molecular basis of MIDY, but may also play an important role in the development and progression of type 1 and type 2 diabetes (2,(24)(25)(26)(27). Increased proinsulin misfolding has been recently reported in b-cells with either defects in the ER folding environment (28)(29)(30), or defective ER export machinery (18), or proinsulin oversynthesis due to insulin resistance in rodent and human type 2 diabetes islets (19). These data suggest that proinsulin misfolding is an early event in the progression to type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Role of Proinsulin Self-Association in MutantINSgene-induced Diabetes of Youth

Sun

Xiong

et al. 2019

Preprint

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Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin in the endoplasmic reticulum (ER) drive the molecular pathogenesis of Mutant-INS-gene induced Diabetes of Youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, proinsulin-WT dimerizes in the ER. Here, we suggest that the normal proinsulin-proinsulin contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that proinsulin Tyr-B16, which is a key residue in normal proinsulin dimerization, helps confer dominant-negative behavior of MIDY mutant proinsulin-C(A7)Y. Substitutions of Tyr-B16 with ether Ala, Asp, or Pro in proinsulin-C(A7)Y each decrease the abnormal interactions between the MIDY mutant and proinsulin-WT, rescuing proinsulin-WT export, limiting ER stress, and increasing insulin production in b-cells and human islets.This study reveals the first evidence indicating that noncovalent proinsulin-proinsulin contact initiates dominant-negative behavior of misfolded proinsulin, pointing to a novel therapeutic target to enhance bystander proinsulin export for increased insulin production.

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Section: Discussionmentioning

confidence: 99%

Role of Proinsulin Self-Association in MutantINSgene-induced Diabetes of Youth

Sun

Xiong

et al. 2019

Preprint

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“…There is strong reason to believe that the time during which proinsulin is most susceptible to misfolding is immediately upon translocation, prior to the completion of chaperone‐ and oxidoreductase‐assisted folding. During this period, WT proinsulin in healthy β‐cells is known to form disulphide‐linked proinsulin complexes . Ultimately, it will be important to develop assays that can establish whether such complexes that persist for more than a few minutes after synthesis are true folding intermediates from which native proinsulin is still recoverable—or do they represent folded states that are irremediably “off pathway”?…”

Section: Future Perspectivesmentioning

confidence: 99%

“…During this period, WT proinsulin in healthy β-cells is known to form disulphide-linked proinsulin complexes. 286 Ultimately, it will be important to develop assays that can establish whether such complexes that persist for more than a few minutes after synthesis are true folding intermediates from which native proinsulin is still recoverable-or do they represent folded states that are irremediably "off pathway"?…”

Section: Future Perspectivesmentioning

confidence: 99%

Biosynthesis, structure, and folding of the insulin precursor protein

Liu

Weiss

Arunagiri

et al. 2018

Diabetes Obesity Metabolism

144

155

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Insulin synthesis in pancreatic β-cells is initiated as preproinsulin. Prevailing glucose concentrations, which oscillate pre- and postprandially, exert major dynamic variation in preproinsulin biosynthesis. Accompanying upregulated translation of the insulin precursor includes elements of the endoplasmic reticulum (ER) translocation apparatus linked to successful orientation of the signal peptide, translocation and signal peptide cleavage of preproinsulin-all of which are necessary to initiate the pathway of proper proinsulin folding. Evolutionary pressures on the primary structure of proinsulin itself have preserved the efficiency of folding ("foldability"), and remarkably, these evolutionary pressures are distinct from those protecting the ultimate biological activity of insulin. Proinsulin foldability is manifest in the ER, in which the local environment is designed to assist in the overall load of proinsulin folding and to favour its disulphide bond formation (while limiting misfolding), all of which is closely tuned to ER stress response pathways that have complex (beneficial, as well as potentially damaging) effects on pancreatic β-cells. Proinsulin misfolding may occur as a consequence of exuberant proinsulin biosynthetic load in the ER, proinsulin coding sequence mutations, or genetic predispositions that lead to an altered ER folding environment. Proinsulin misfolding is a phenotype that is very much linked to deficient insulin production and diabetes, as is seen in a variety of contexts: rodent models bearing proinsulin-misfolding mutants, human patients with Mutant INS-gene-induced Diabetes of Youth (MIDY), animal models and human patients bearing mutations in critical ER resident proteins, and, quite possibly, in more common variety type 2 diabetes.

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“…However, it remained unclear whether this protein has physiological functions other than binding estrogen. To solve this question, we set out to identify the physiological substrates of this enzyme from a mouse tissue, utilizing the fact that PDI family members often form disulfide-linked complexes with their target proteins (15,31). Our analysis on the role of PDIp in the biosynthesis of one of the identified proteins led to a clue as to the physiological function of this enzyme.…”

Section: Discussionmentioning

confidence: 99%

Identification of the physiological substrates of PDIp, a pancreas-specific protein-disulfide isomerase family member

Fujimoto

Nakamura

Saito

et al. 2018

Journal of Biological Chemistry

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Edited by Ruma Banerjee About 20 members of the protein-disulfide isomerase (PDI) family are present in the endoplasmic reticulum of mammalian cells. They are thought to catalyze thiol-disulfide exchange reactions within secretory or membrane proteins to assist in their folding or to regulate their functions. PDIp is a PDI family member highly expressed in the pancreas and known to bind estrogen in vivo and in vitro. However, the physiological functions of PDIp remained unclear. In this study, we set out to identify its physiological substrates. By combining acid quenching and thiol alkylation, we stabilized and purified the complexes formed between endogenous PDIp and its target proteins from the mouse pancreas. MS analysis of these complexes helped identify the disulfide-linked PDIp targets in vivo, revealing that PDIp interacts directly with a number of pancreatic digestive enzymes. Interestingly, when pancreatic elastase, one of the identified proteins, was expressed alone in cultured cells, its proenzyme formed disulfide-linked aggregates within cells. However, when pancreatic elastase was co-expressed with PDIp, the latter prevented the formation of these aggregates and enhanced the production and secretion of proelastase in a form that could be converted to an active enzyme upon trypsin treatment. These findings indicate that the main targets of PDIp are digestive enzymes and that PDIp plays an important role in the biosynthesis of a digestive enzyme by assisting with the proper folding of the proenzyme within cells. This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grants JP15K07381 (to H. K.), JP15H04335 (to K. I.), and JP24228002 (to K. K.); Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI Grant JP26116005 (to H. K. and K. I.); and CREST Grant JPMJCR13M6 (to K. I.). This work was also supported, in part, by a grant from the Noda Institute for Scientific Research (to H. K.). The authors declare that they have no conflicts of interest with the contents of this article. This article contains Tables S1 and S2 and Figs. S1 and S2.

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IRE1–XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells

Cited by 88 publications

References 53 publications

Role of Proinsulin Self-Association in MutantINSgene-induced Diabetes of Youth

Role of Proinsulin Self-Association in MutantINSgene-induced Diabetes of Youth

Biosynthesis, structure, and folding of the insulin precursor protein

Identification of the physiological substrates of PDIp, a pancreas-specific protein-disulfide isomerase family member

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