RRC ID 49233
Author Jegal KH, Park SM, Cho SS, Byun SH, Ku SK, Kim SC, Ki SH, Cho IJ.
Title Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury.
Journal Biochim Biophys Acta Mol Cell Res
Abstract Endoplasmic reticulum (ER) stress is characterized by an accumulation of misfolded proteins, and ER stress reduction is essential for maintaining tissue homeostasis. However, the molecular mechanisms that protect cells from ER stress are not completely understood. The present study investigated the role of sestrin 2 (SESN2) on ER stress and sought to elucidate the mechanism responsible for the hepatoprotective effect of SESN2 in vitro and in vivo. Treatment with tunicamycin (Tm) increased SESN2 protein and mRNA levels and reporter gene activity. Activating transcription factor 6 (ATF6) bound to unfolded protein response elements of SESN2 promoter, transactivated SESN2, and increased SESN2 protein expression. In addition, dominant negative mutant of ATF6α and siRNA against ATF6α blocked the ER stress-mediated SESN2 induction, whereas chemical inhibition of PERK or IRE1 did not affect SESN2 induction by Tm. Ectopic expression of SESN2 in HepG2 cells inhibited CHOP and GRP78 expressions by Tm. Moreover, SESN2 decreased the phosphorylations of JNK and p38 and PARP cleavage, and blocked the cytotoxic effect of excessive ER stress. In a Tm-induced liver injury model, adenoviral delivery of SESN2 in mice decreased serum ALT, AST and LDH activities and the mRNA levels of CHOP and GRP78 in hepatic tissues. Moreover, SESN2 reduced numbers of degenerating hepatocytes, and inhibited caspase 3 and PARP cleavages. These results suggest ATF6 is essential for ER stress-mediated SESN2 induction, and that SESN2 acts as a feedback regulator to protect liver from excess ER stress.
Volume 1864(7)
Pages 1295-1307
Published 2017-7-1
DOI 10.1016/j.bbamcr.2017.04.010
PII S0167-4889(17)30104-0
PMID 28433684
MeSH Activating Transcription Factor 6 / metabolism* Animals Apoptosis Chemical and Drug Induced Liver Injury / etiology Chemical and Drug Induced Liver Injury / metabolism* Endoplasmic Reticulum Chaperone BiP Endoplasmic Reticulum Stress* HEK293 Cells Hep G2 Cells Hepatocytes / drug effects Hepatocytes / metabolism Humans MAP Kinase Kinase 4 / metabolism MAP Kinase Signaling System Male Mice Mice, Inbred ICR Nuclear Proteins / genetics Nuclear Proteins / metabolism* Peroxidases Tunicamycin / toxicity p38 Mitogen-Activated Protein Kinases / metabolism
IF 3.411
Times Cited 10
DNA material pGL4-phSESN2 (RDB07413)