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Unbiased Profiling of the Human Proinsulin Biosynthetic Interaction Network Reveals a Role for Peroxiredoxin 4 in Proinsulin Folding

Overview
Journal Diabetes
Specialty Endocrinology
Date 2020 May 28
PMID 32457219
Citations 12
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Abstract

The β-cell protein synthetic machinery is dedicated to the production of mature insulin, which requires the proper folding and trafficking of its precursor, proinsulin. The complete network of proteins that mediate proinsulin folding and advancement through the secretory pathway, however, remains poorly defined. Here we used affinity purification and mass spectrometry to identify, for the first time, the proinsulin biosynthetic interaction network in human islets. Stringent analysis established a central node of proinsulin interactions with endoplasmic reticulum (ER) folding factors, including chaperones and oxidoreductases, that is remarkably conserved in both sexes and across three ethnicities. The ER-localized peroxiredoxin PRDX4 was identified as a prominent proinsulin-interacting protein. In β-cells, gene silencing of PRDX4 rendered proinsulin susceptible to misfolding, particularly in response to oxidative stress, while exogenous PRDX4 improved proinsulin folding. Moreover, proinsulin misfolding induced by oxidative stress or high glucose was accompanied by sulfonylation of PRDX4, a modification known to inactivate peroxiredoxins. Notably, islets from patients with type 2 diabetes (T2D) exhibited significantly higher levels of sulfonylated PRDX4 than islets from healthy individuals. In conclusion, we have generated the first reference map of the human proinsulin interactome to identify critical factors controlling insulin biosynthesis, β-cell function, and T2D.

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References
1.
Zhang L, Lanzoni G, Battarra M, Inverardi L, Zhang Q . Proteomic profiling of human islets collected from frozen pancreata using laser capture microdissection. J Proteomics. 2016; 150:149-159. PMC: 5110395. DOI: 10.1016/j.jprot.2016.09.002. View

2.
Schrimpe-Rutledge A, Fontes G, Gritsenko M, Norbeck A, Anderson D, Waters K . Discovery of novel glucose-regulated proteins in isolated human pancreatic islets using LC-MS/MS-based proteomics. J Proteome Res. 2012; 11(7):3520-32. PMC: 3391329. DOI: 10.1021/pr3002996. View

3.
Orci L, Ravazzola M, Perrelet A . (Pro)insulin associates with Golgi membranes of pancreatic B cells. Proc Natl Acad Sci U S A. 1984; 81(21):6743-6. PMC: 392007. DOI: 10.1073/pnas.81.21.6743. View

4.
Braakman I, Bulleid N . Protein folding and modification in the mammalian endoplasmic reticulum. Annu Rev Biochem. 2011; 80:71-99. DOI: 10.1146/annurev-biochem-062209-093836. View

5.
Choi M, Chang C, Clough T, Broudy D, Killeen T, MacLean B . MSstats: an R package for statistical analysis of quantitative mass spectrometry-based proteomic experiments. Bioinformatics. 2014; 30(17):2524-6. DOI: 10.1093/bioinformatics/btu305. View