Journal
JOURNAL OF MOLECULAR CELL BIOLOGY
Volume 8, Issue 2, Pages 144-156Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jmcb/mjv066
Keywords
IRE1; RACK1; AMPK; BCL2; ER stress preconditioning; ischemia/reperfusion injury
Categories
Funding
- National Natural Science Foundation of China [81070363, 30900497, 31271518, 31471275, 31301121, 31471268, 31501095, 31320103904]
- National Institutes of Health [CA164133, DK56292]
- Anhui Provincial Natural Science Foundation [1508085SMC213]
- China Postdoctoral Science Foundation [2014M560517]
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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 liverbyactivatinginositol-requiringenzyme1(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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