生物
表型
衰老
细胞生物学
压力(语言学)
遗传学
基因
语言学
哲学
作者
Matthew J. Payea,Showkat Ahmad Dar,Carlos Anerillas,Jennifer L. Martindale,Cédric Belair,Rachel Munk,Sulochan Malla,Jinshui Fan,Yulan Piao,Xiaoling Yang,Abid Ur Rehman,Nirad Banskota,Kotb Abdelmohsen,Myriam Gorospe,Manolis Maragkakis
标识
DOI:10.1016/j.molcel.2024.10.003
摘要
Senescence is a state of indefinite cell-cycle arrest associated with aging, cancer, and age-related diseases. Here, we find that translational deregulation, together with a corresponding maladaptive integrated stress response (ISR), is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response activating transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames (uORFs). Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. We also find that stress augments the senescence-associated secretory phenotype with sustained remodeling of inflammatory factors expression that is suppressed by non-uORF carrying ATF4 mRNA expression. Our results thus show that senescent cells possess a unique response to stress, which entails an increase in their inflammatory profile.
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