The p38‐activated ER stress‐ATF6α axis mediates cellular senescence

Abstract

The importance of proteostasis in preventing cellular senescence has been well recognized. However, the exact mechanism by which the loss of proteostasis or endoplasmic reticulum (ER) stress induces cellular senescence remains unclear. We report that ER stress mediates cellular senescence through the activating transcription factor (ATF)6α branch of the unfolded protein response (UPR). Cellular senescence was induced by the abrogation of neighbor of breast cancer (BRCA)1 gene (NBR1). NBR1 abrogation‐induced senescence was p53 dependent and observed in both transformed and nontransformed human cell lines: MCF‐7, Caki‐1, and MRC‐5. NBR1 bound to p38 MAPK, preferentially to an active form, and upon NBR1 abrogation, the activity of p38 increased. NADPH oxidase was activated in turn by p38, and the resulting oxidative stress triggered ER stress. It was found that ER stress mediated cellular senescence through the UPR sensor ATF6α. Knockdown of ATF6α prevented senescence, whereas ATF6α overexpression triggered it. The transcriptional activity of ATF6α was important. The ER stress‐ATF6α axis also mediated cellular senescence induced by H‐RasV12 overexpression and UV irradiation, suggesting a common role of this axis in senescence induction. In summary, we presented an evidence for the novel role of the ER stress‐ATF6α axis in cellular senescence.—Kim, H. S., Kim, Y., Lim, M. J., Park, Y.‐G., Park, S. I., Sohn, J. The p38‐activated ER stress‐ATF6α axis mediates cellular senescence. FASEB J. 33, 2422–2434 (2019). http://www.fasebj.org

Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease

“…It is also well recognized that proteostasis prevents cellular senescence (Kim et al., 2018), and senescent cells can contribute to age‐related tissue degeneration and fat accumulation (Ogrodnik et al., 2017). Therefore, we also analyzed markers of senescence in 10m mice livers.…”

Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer

“…The involvement of ER stress in the senescence process has been established: p38 MAPK is well known to be involved in cellular senescence, its activation triggered ER stress and resulted in senescence by upregulating unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6α) in both transformed and nontransformed cells. The ER stress/ATF6α axis also mediated cellular senescence induced by RAS overexpression and UV irradiation [98].…”

Aging and stress induced β cell senescence and its implication in diabetes development

“…Importantly, unlike other cell types, β cells manifest relatively lower antioxidant capability and, as a result, they are more susceptible to oxidative stress and endoplasmic reticulum (ER) stress [33–35]. Excessive reactive oxygen species (ROS) production impairs mitochondrial dynamics (fission and fusion), leading to defective electron transport chain, bioenergetics imbalance, and altered mitochondria calcium homeostasis, which then trigger β cell senescence [36–38]. It is noteworthy that mitochondria-related senescence is featured by the lack of IL1-arm cytokines, due to high AMP to ATP ratio in the mitochondria coupled with highly activated AMPK, which in turn represses the initiation of mTORC1 and IL1-arm cytokine responses [39].…”

“…Increased protein synthesis load, oxidative stress, gene mutations, glucolipotoxicity, can cause ER tress in β cells. The activation of the three branches of unfolded protein response accelerates cellular senescence in non-β cell types, and the ER chaperone, Bip, has a possible central role in senescence [38, 40]. Therefore, it is quite possible that ER stress actively participates in β cell senescence despite the unclear molecular mechanisms.…”

“…More recently, studies indicated that β cell senescence can be affected by proximal pancreatic cells namely acinar cells and other hormonal factors. It was noted that the expression of arginase II in acinar cells increases during aging process, and enhanced TNF-α release from acinar cells induces β cell dysfunction and apoptosis [38]. Since β cell senescence can be disseminated by surrounding β cells, a crosstalk may exist between β cells and other types of pancreatic cells, thereby regulating β cell senescence.…”