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2015 ; 8
(382
): ra62
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IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death
under pathological conditions
#MMPMID26106220
Kanekura K
; Ma X
; Murphy JT
; Zhu LJ
; Diwan A
; Urano F
Sci Signal
2015[Jun]; 8
(382
): ra62
PMID26106220
show ga
The endoplasmic reticulum (ER) has emerged as a critical regulator of cell
survival. IRE1 is a transmembrane protein with kinase and RNase activities that
is localized to the ER and that promotes resistance to ER stress. We showed a
mechanism by which IRE1 conferred protection against ER stress-mediated cell
death. IRE1 signaling prevented ER membrane permeabilization mediated by Bax and
Bak and cell death in cells experiencing ER stress. Suppression of IRE1 signaling
triggered by its kinase activity led to the accumulation of the BH3
domain-containing protein Bnip3, which in turn triggered the oligomerization of
Bax and Bak in the ER membrane and ER membrane permeabilization. Consequently, in
response to ER stress, cells deficient in IRE1 were susceptible to leakage of ER
contents, which was associated with the accumulation of calcium in mitochondria,
oxidative stress in the cytosol, and ultimately cell death. Our results reveal a
role for IRE1 in preventing a cell death-initializing step that emanates from the
ER and provide a potential target for treating diseases characterized by ER
stress, including diabetes and Wolfram syndrome.