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Impaired Cleavage of Preproinsulin Signal Peptide Linked to Autosomal-Dominant Diabetes

Liu, Ming and Lara-Lemus, Roberto and Shan, Shu-ou and Wright, Jordan and Haataja, Leena and Barbetti, Fabrizio and Guo, Huan and Larkin, Dennis and Arvan, Peter (2012) Impaired Cleavage of Preproinsulin Signal Peptide Linked to Autosomal-Dominant Diabetes. Diabetes, 61 (4). pp. 828-837. ISSN 0012-1797 . PMCID PMC3314357. https://resolver.caltech.edu/CaltechAUTHORS:20120502-085929510

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Abstract

Recently, missense mutations upstream of preproinsulin’s signal peptide (SP) cleavage site were reported to cause mutant INS gene-induced diabetes of youth (MIDY). Our objective was to understand the molecular pathogenesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production to examine the earliest events of insulin biosynthesis, highlighting molecular mechanisms underlying β-cell failure plus a novel strategy that might ameliorate the MIDY syndrome. We find that whereas preproinsulin-A(SP23)S is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is inefficiently cleaved at an improper site, producing two subpopulations of molecules. Both show impaired oxidative folding and are retained in the endoplasmic reticulum (ER). Preproinsulin-A(SP24)D also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavior. Upon increased expression of ER–oxidoreductin-1, preproinsulin-A(SP24)D remains blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and increasing wild-type insulin production. We conclude that the efficiency of SP cleavage is linked to the oxidation of (pre)proinsulin. In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as well as that of coexpressed wild-type proinsulin. Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin production in patients with MIDY.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.2337/db11-0878 DOIArticle
http://diabetes.diabetesjournals.org/content/61/4/828PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314357/PubMed CentralArticle
ORCID:
AuthorORCID
Shan, Shu-ou0000-0002-6526-1733
Additional Information:© 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. Received June 24, 2011. Accepted December 19, 2011. This work was supported primarily by National Institutes of Health (NIH) grants R01-DK-48280 (to P.A.) and R01-DK-088856 and by March of Dimes 6-FY11-357 (to M.L.) as well as National Nature Science Foundation of China Grant 81070629 (to M.L.). We also acknowledge assistance from the Molecular Biology and DNA Sequencing Core of the NIH-funded Diabetes Research and Training Center (P60-DK-20572). No potential conflicts of interest relevant to this article were reported. Author Contributions: M.L., R.L.-L., J.W., L.H., H.G., and D.L. researched data. M.L., S.-o.S., J.W., L.H., F.B., and P.A. contributed to discussion. M.L. and P.A. wrote the manuscript. M.L., J.W., F.B., and P.A. reviewed and edited the manuscript. P.A. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors thank Bill and Dee Brehm for helping to create the Brehm Center for Diabetes Research to advance diabetes research at the University of Michigan.
Funders:
Funding AgencyGrant Number
NIHR01-DK-48280
NIHR01-DK-088856
March of Dimes6-FY11-357
National Nature Science Foundation of China81070629
NIHP60-DK-20572
Issue or Number:4
PubMed Central ID:PMC3314357
Record Number:CaltechAUTHORS:20120502-085929510
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120502-085929510
Usage Policy:Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details.
ID Code:31266
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 May 2012 17:11
Last Modified:03 Oct 2019 03:50

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