title: IRE1-RACK1 axis orchestrates ER stress preconditioning-elicited cytoprotection from ischemia/reperfusion injury in liver.
abstract: 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.
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China Present address: Department of Hepatobiliary Surgery, Navy General Hospital, Beijing 100048, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Anhui Key Laboratory of Cellular Dynamics and Hefei National Laboratory for Physical Sciences at Nanoscale, Hefei 230027, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Atlanta Clinical & Translational Science Institute, Atlanta, GA 30310, USA.
authors.forename: William
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Anhui Key Laboratory of Cellular Dynamics and Hefei National Laboratory for Physical Sciences at Nanoscale, Hefei 230027, China Atlanta Clinical & Translational Science Institute, Atlanta, GA 30310, USA Department of Biochemistry, Anhui Medical University, Hefei 230027, China.
authors.forename: Fengsong
authors.initials: F
authors.lastname: Wang
authors.affiliation: Atlanta Clinical & Translational Science Institute, Atlanta, GA 30310, USA.
authors.forename: Felix O
authors.initials: FO
authors.lastname: Aikhionbare
authors.affiliation: Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Hill
authors.affiliation: Atlanta Clinical & Translational Science Institute, Atlanta, GA 30310, USA.
authors.forename: Nerimah
authors.initials: N
authors.lastname: Emmett
authors.affiliation: Anhui Key Laboratory of Cellular Dynamics and Hefei National Laboratory for Physical Sciences at Nanoscale, Hefei 230027, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Anhui Key Laboratory of Cellular Dynamics and Hefei National Laboratory for Physical Sciences at Nanoscale, Hefei 230027, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.affiliation: Atlanta Clinical & Translational Science Institute, Atlanta, GA 30310, USA yongchen62@yahoo.com xyao@msm.edu.
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China yongchen62@yahoo.com xyao@msm.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1 / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D008099:Liver / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000071186:Beclin-1; C512829:Becn1 protein, rat; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D014415:Tunicamycin; C486557:Ern2 protein, rat; D017346:Protein Serine-Threonine Kinases; D000263:Adenylate Kinase
keywords: AMPK; BCL2; ER stress preconditioning; IRE1; RACK1; ischemia/reperfusion injury