Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury

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.

The Emerging Role of Sestrin2 in Cell Metabolism, and Cardiovascular and Age-Related Diseases

“…Conversely, if Sesn2 is lacking, cells are highly susceptible to ER stress-associated cell death due to the continued translation of large amounts of protein [14]. A recent study indicated that the induction of Sesn2 under ER stress is dependent on activating transcription factor 6, and Sesn2 plays a hepatoprotective role in the presence of excess ER stress by inhibiting CCAAT-enhancer-binding protein homologous protein, c-Jun N-terminal kinase (JNK), and p38 [40]. ER stress is an aspect of the pathogenesis of aging and a variety of human diseases, such as cardiovascular diseases; however, the transcription factors involved in the induction of Sesn2 by ER stress and the protective mechanisms triggered by Sesn2 against ER stressmediated cell death require further exploration.…”

Emerging Roles of Sestrins in Neurodegenerative Diseases: Counteracting Oxidative Stress and Beyond

“…It was originally found that the expression of sestrin1 and sestrin2 was regulated by p53 [6], whereas the expression of sestrin3 was regulated by transcription factor forkhead box O (FOXO) [21,22]. Later, additional studies reveal several regulators crucial for the expression of sestrins under various stressful conditions; these include nuclear factor erythroid 2 like 2 (Nrf2), activating transcription factor4 (ATF4), ATF6, c-Jun N-terminal kinase (JNK)/c-Jun pathway, hypoxia-inducible factor-1α (HIF-1α), X-box-binding protein 1 (XBP1), and CCAAT/enhancer-binding protein beta (C/EBPβ) [23,24,25,26,27,28]. Together, these previous reports imply vital roles of sestrins in coping with cellular stress under different physiological and pathological conditions.…”

Sestrin2 protects dendritic cells against endoplasmic reticulum stress-related apoptosis induced by high mobility group box-1 protein

“…It was reported that SESNs protected cells against various stimuli by regulating autophagy, ERS, metabolism, and apoptosis. As the unique protein in SESNs family, SESN2 was found to be upregulated by the activation of ERS signaling pathways and be an important protective factor on relieving cell injury and cell death [19][20][21][22][23][24] . We proposed that SESN2 might be one of the favorable factors in immune regulation of DCs under ERS in the setting of sepsis.…”