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题名:Endoplasmic Reticulum Oxidoreductin-1alpha (Ero1alpha) Improves Folding and Secretion of Mutant Proinsulin and Limits Mutant Proinsulin-induced Endoplasmic Reticulum Stress.
作者:WRIGHT J; BIRK J; HAATAJA L; LIU M; RAMMING T; WEISS MA; APPENZELLER-HERZOG C; ARVAN P;
来源:J Biol Chem. 2013 Oct 25;288(43):31010-8. doi: 10.1074/jbc.M113.510065. Epub 2013 [ IF= 0.00 ] ]
URL :10.1074/jbc.M113.510065
日期:20131104
摘要:Upon chronic up-regulation of proinsulin synthesis, misfolded proinsulin can
accumulate in the endoplasmic reticulum (ER) of pancreatic beta-cells, promoting
ER stress and type 2 diabetes mellitus. In Mutant Ins-gene-induced Diabetes of
Youth (MIDY), misfolded mutant proinsulin impairs ER exit of co-expressed
wild-type proinsulin, limiting insulin production and leading to eventual
beta-cell death. In this study we have investigated the hypothesis that increased
expression of ER oxidoreductin-1alpha (Ero1alpha), despite its established role
in the generation of H2O2, might nevertheless be beneficial in limiting
proinsulin misfolding and its adverse downstream consequences. Increased
Ero1alpha expression is effective in promoting wild-type proinsulin export from
cells co-expressing misfolded mutant proinsulin. In addition, we find that upon
increased Ero1alpha expression, some of the MIDY mutants themselves are directly
rescued from ER retention. Secretory rescue of proinsulin-G(B23)V is correlated
with improved oxidative folding of mutant proinsulin. Indeed, using three
different variants of Ero1alpha, we find that expression of either wild-type or
an Ero1alpha variant lacking regulatory disulfides can rescue mutant
proinsulin-G(B23)V, in parallel with its ability to provide an oxidizing
environment in the ER lumen, whereas beneficial effects were less apparent for a
redox-inactive form of Ero1. Increased expression of protein disulfide isomerase
antagonizes the rescue provided by oxidatively active Ero1. Importantly, ER
stress induced by misfolded proinsulin was limited by increased expression of
Ero1alpha, suggesting that enhancing the oxidative folding of proinsulin may be a
viable therapeutic strategy in the treatment of type 2 diabetes.

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