Tags

Type your tag names separated by a space and hit enter

Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury.
Biochim Biophys Acta Mol Cell Res. 2017 Jul; 1864(7):1295-1307.BB

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.

Authors+Show Affiliations

College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea. Electronic address: shki@chosun.ac.kr.College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea. Electronic address: skek023@dhu.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28433684

Citation

Jegal, Kyung Hwan, et al. "Activating Transcription Factor 6-dependent Sestrin 2 Induction Ameliorates ER Stress-mediated Liver Injury." Biochimica Et Biophysica Acta. Molecular Cell Research, vol. 1864, no. 7, 2017, pp. 1295-1307.
Jegal KH, Park SM, Cho SS, et al. Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury. Biochim Biophys Acta Mol Cell Res. 2017;1864(7):1295-1307.
Jegal, K. H., Park, S. M., Cho, S. S., Byun, S. H., Ku, S. K., Kim, S. C., Ki, S. H., & Cho, I. J. (2017). Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury. Biochimica Et Biophysica Acta. Molecular Cell Research, 1864(7), 1295-1307. https://doi.org/10.1016/j.bbamcr.2017.04.010
Jegal KH, et al. Activating Transcription Factor 6-dependent Sestrin 2 Induction Ameliorates ER Stress-mediated Liver Injury. Biochim Biophys Acta Mol Cell Res. 2017;1864(7):1295-1307. PubMed PMID: 28433684.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury. AU - Jegal,Kyung Hwan, AU - Park,Sang Mi, AU - Cho,Sam Seok, AU - Byun,Sung Hui, AU - Ku,Sae Kwang, AU - Kim,Sang Chan, AU - Ki,Sung Hwan, AU - Cho,Il Je, Y1 - 2017/04/19/ PY - 2016/11/15/received PY - 2017/04/14/revised PY - 2017/04/18/accepted PY - 2017/4/24/pubmed PY - 2017/10/25/medline PY - 2017/4/24/entrez KW - Activating transcription factor 6 (ATF6) KW - Endoplasmic reticulum (ER) stress KW - Sestrin 2 (SESN2) KW - Tunicamycin-induced liver injury SP - 1295 EP - 1307 JF - Biochimica et biophysica acta. Molecular cell research JO - Biochim Biophys Acta Mol Cell Res VL - 1864 IS - 7 N2 - 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. SN - 0167-4889 UR - https://www.unboundmedicine.com/medline/citation/28433684/Activating_transcription_factor_6_dependent_sestrin_2_induction_ameliorates_ER_stress_mediated_liver_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0167-4889(17)30104-0 DB - PRIME DP - Unbound Medicine ER -