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Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes

Guo, Huan and Xiong, Yi and Witkowski, Piotr and Cui, Jingqing and Wang, Ling-jia and Sun, Jinhong and Lara-Lemus, Roberto and Haataja, Leena and Hutchison, Kathryn and Shan, Shu-ou and Arvan, Peter and Liu, Ming (2014) Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes. Journal of Biological Chemistry, 289 (23). pp. 16290-16302. ISSN 0021-9258. PMCID PMC4047398.

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Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of β cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of a positive charge in the n region of its signal sequence) contributes to β cell failure and diabetes. Specifically, we find that, after targeting to the ER membrane, preproinsulin signal peptide (SP) mutants associated with autosomal dominant late-onset diabetes fail to be fully translocated across the ER membrane. The newly synthesized, untranslocated preproinsulin remains strongly associated with the ER membrane, exposing its proinsulin moiety to the cytosol. Rather than accumulating in the ER and inducing ER stress, untranslocated preproinsulin accumulates in a juxtanuclear compartment distinct from the Golgi complex, induces the expression of heat shock protein 70 (HSP70), and promotes β cell death. Restoring an N-terminal positive charge to the mutant preproinsulin SP significantly improves the translocation defect. These findings not only reveal a novel molecular pathogenesis of β cell failure and diabetes but also provide the first evidence of the physiological and pathological significance of the SP n region positive charge of secretory proteins.

Item Type:Article
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Shan, Shu-ou0000-0002-6526-1733
Additional Information:© 2014 The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, March 2, 2014, and in revised form, March 26, 2014 Published, JBC Papers in Press, April 25, 2014. We thank Bill and Dee Brehm for helping to establish the Brehm Center for Diabetes Research at the University of Michigan and Drs. Donald F. Steiner, Michael A. Weiss, Graeme Bell, and Yanzhuang Wang for encouragement and discussions. We also thank Dr. Martin Jendrisak and the entire team of the Gift of Hope Organ and Tissue Donor Network in Chicago for the human pancreas tissues used in this study. This work was supported, in whole or in part, by National Institutes of Health Grants RO1-DK088856 (to M. L.), RO1-DK-48280 (to P. A.), RO1 GM078024 (to S. S.), and P60-DK-20572 (to the Molecular Biology and DNA Sequencing Core of the Diabetes Research and Training Center). This work was also supported by National Natural Science Foundation of China Research Grant 81070629 (to M. L.), by a research grant from the March of Dimes Foundation (to M. L.), and by the Protein Folding Disease Initiatives of the University of Michigan. Human pancreatic islet processing was supported by Illinois Department of Public Health Grant “Pancreatic Islets Transplantation.”
Funding AgencyGrant Number
National Nature Science Foundation of China81070629
March of Dimes FoundationUNSPECIFIED
University of MichiganUNSPECIFIED
Illinois Department of Public HealthUNSPECIFIED
Subject Keywords:β Cell; Diabetes; Insulin Synthesis; Mutant; Protein Translocation; Cytosolic Protein Accumulation; Preproinsulin; Proinsulin
Issue or Number:23
PubMed Central ID:PMC4047398
Record Number:CaltechAUTHORS:20140728-091816472
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Official Citation:Guo, H., Xiong, Y., Witkowski, P., Cui, J., Wang, L.-j., Sun, J., . . . Liu, M. (2014). Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes. Journal of Biological Chemistry, 289(23), 16290-16302. doi: 10.1074/jbc.M114.562355
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:47517
Deposited By: Jason Perez
Deposited On:28 Jul 2014 17:22
Last Modified:03 Oct 2019 06:54

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