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IRE1-RACK1 axis orchestrates ER stress preconditioning-elicited cytoprotection
from ischemia/reperfusion injury in liver
#MMPMID26711306
Liu D
; Liu X
; Zhou T
; Yao W
; Zhao J
; Zheng Z
; Jiang W
; Wang F
; Aikhionbare FO
; Hill DL
; Emmett N
; Guo Z
; Wang D
; Yao X
; Chen Y
J Mol Cell Biol
2016[Apr]; 8
(2
): 144-56
PMID26711306
show ga
Endoplasmic reticulum (ER) stress is involved in ischemic preconditioning that
protects various organs from ischemia/reperfusion (I/R) injury. We established an
in vivo ER stress preconditioning model in which tunicamycin was injected into
rats before hepatic I/R. The hepatic I/R injury, demonstrated by serum
aminotransferase level and the ultra-structure of the liver, was alleviated by
administration of tunicamycin, which induced ER stress in rat liver by activating
inositol-requiring enzyme 1 (IRE1) and upregulating 78 kDa glucose-regulated
protein (GRP78). The proteomic identification for IRE1 binders revealed
interaction and cooperation among receptor for activated C kinase 1 (RACK1),
phosphorylated AMPK, and IRE1 under ER stress conditions in a spatiotemporal
manner. Furthermore, in vitro ER stress preconditioning was induced by
thapsigargin and tunicamycin in L02 and HepG2 cells. Surprisingly, BCL2 was found
to be phosphorylated by IRE1 under ER stress conditions to prevent apoptotic
process by activation of autophagy. In conclusion, ER stress preconditioning
protects against hepatic I/R injury, which is orchestrated by IRE1-RACK1 axis
through the activation of BCL2. Our findings provide novel insights into the
molecular pathways underlying ER stress preconditioning-elicited cytoprotective
effect against hepatic I/R injury.
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