Senescent Cells Are Resistant to Activation of the Integrated Stress Response Pathway

FARE Award Winner

Authors

• MJ Payea
• S Dar
• C Belair
• JM Martindale
• RB Munk
• M Maragkakis

Abstract

Cellular senescence occurs in response to sub-lethal genomic damage and is a central mechanism of aging. Senescence can be induced in any cell type and senescent cells accumulate during aging where they contribute to aging-related disease through a persistent inflammatory program called the Senescence Associated Secretory Phenotype (SASP). The SASP is activated through continuous DNA damage signaling that promotes expression of secretory proteins, thus placing senescent cells in a state of constant unresolved stress. To examine the role of stress in senescence, we conducted a proteomic screen of senescent, quiescent, and cycling cells. We found senescence-specific increases in numerous ER stress response proteins and further investigation showed increased phosphorylation of the translation initiation factor eIF2α, which is a marker of integrated stress response (ISR) activation. However, senescent cells did not express the ISR transcription factor ATF4, even after overexpression of an in vitro transcribed ATF4 mRNA. Ribosome-sequencing analysis revealed that senescent cells failed to bypass the inhibitory upstream ORFs of ATF4 that is normally mediated by eIF2α-P, suggesting that elevated eIF2α-P levels were insufficient to activate the ISR in senescence. In fact, senescent cells showed extreme resistance to expression of ATF4 in response to exogenous oxidative, proteotoxic, and starvation stressors indicating that the ISR response is highly inhibited during senescence. We further found that senescent cells survived even lethal amounts of stress compared to cycling cells and entered a hypersecretory state that lasts long after the stressor was removed.

Scientific Focus Area: Cell Biology

This page was last updated on Monday, September 25, 2023