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题名:Endoplasmic Reticulum Oxidoreductin-1alpha (Ero1alpha) Improves Folding and Secretion of Mutant Proinsulin and Limits Mutant Proinsulin-Induced ER 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 Sep 10. [ IF= 0.00 ] ]
URL :10.1074/jbc.M113.510065
日期:20131002
摘要:Upon chronic upregulation 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
wildtype 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 1 alpha (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 wildtype 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 wildtype 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
(PDI) 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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