IRE1-RACK1 axis orchestrates ER stress preconditioning-elicited cytoprotection from ischemia/reperfusion injury in liver
IRE1-RACK1 axis orchestrates ER stress preconditioning-elicited cytoprotection from ischemia/reperfusion injury in liver
复制标题
IRE1-RACK1轴协调内质网应激预处理引起的肝脏缺血/再灌注损伤的细胞保护作用
DOI：
10.1093/jmcb/mjv066
复制
发表时间：
2016-04-01
影响因子：
5.5
通讯作者：
Chen, Yong
中科院分区：
文献类型：
--
作者：
Liu, Dong;Liu, Xing;Chen, Yong
内质网（ER）应激参与了保护各器官免受缺血/再灌注（I/R）损伤的缺血预处理。采用大鼠肝I/R前注射tunicamycin，建立了大鼠体内内质网应激预处理模型。tunicamycin通过激活肌醇要求酶1（IRE1）和上调78 kDa葡萄糖调节蛋白（GRP78），诱导大鼠肝脏内质网应激，减轻了肝脏I/R损伤。IRE1结合物的蛋白质组学鉴定揭示了内质网应激条件下活化C激酶1 （activated C kinase 1, RACK1）受体、磷酸化AMPK受体和IRE1之间的时空相互作用和合作。此外，在L02和HepG2细胞中，thapsigargin和tunicamycin可诱导体外内质网应激预处理。令人惊讶的是，在内质网应激条件下，BCL2被IRE1磷酸化，通过激活自噬来阻止凋亡过程。综上所述，内质网应激预处理可预防肝脏I/R损伤，该损伤是由IRE1-RACK1轴通过激活BCL2介导的。我们的研究结果为内质网应激预处理引发的抗肝I/R损伤的细胞保护作用的分子途径提供了新的见解。
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.