The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress.

Autor: Anerillas C; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. carlos.anerillasaljama@nih.gov., Mazan-Mamczarz K; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Herman AB; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Munk R; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Lam KG; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Calvo-Rubio M; Translational Gerontology Branch, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Garrido A; Translational Gerontology Branch, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Tsitsipatis D; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Martindale JL; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Altés G; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Rossi M; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Piao Y; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Fan J; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Cui CY; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., De S; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Abdelmohsen K; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., de Cabo R; Translational Gerontology Branch, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Gorospe M; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. myriam-gorospe@nih.gov.
Jazyk: angličtina
Zdroj: Nature aging [Nat Aging] 2023 Oct; Vol. 3 (10), pp. 1237-1250. Date of Electronic Publication: 2023 Sep 04.
DOI: 10.1038/s43587-023-00480-4
Abstrakt: Sublethal cell damage can trigger senescence, a complex adaptive program characterized by growth arrest, resistance to apoptosis and a senescence-associated secretory phenotype (SASP). Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, verteporfin (VPF), selectively triggered apoptotic cell death largely by derepressing DDIT4, which in turn inhibited mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, triggering ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased the numbers of senescent cells in the organs of old mice and mice exhibiting doxorubicin-induced senescence. Moreover, VPF treatment reduced immune cell infiltration and pro-fibrotic transforming growth factor-β signaling in aging mouse lungs, improving tissue homeostasis. We present an alternative senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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