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

Area of Science:

• Cellular biology
• Aging research
• Drug discovery

Background:

• Sublethal cell damage induces senescence, a state of growth arrest with a senescence-associated secretory phenotype (SASP).
• Senescent cells contribute to aging and age-related diseases.
• Targeting senescent cells (senolytics) is a promising therapeutic strategy.

Purpose of the Study:

• To identify novel targets for senolytic therapy.
• To investigate the role of the YAP-TEAD pathway in senescent cell viability.
• To evaluate verteporfin (VPF) as a senolytic agent.

Main Methods:

• Whole-genome CRISPR knockout screen to identify genes influencing senescent cell viability.
• Treatment of senescent cells with verteporfin (VPF), a YAP-TEAD pathway inhibitor.
• Analysis of apoptosis, endoplasmic reticulum (ER) stress, and mTOR signaling.
• In vivo studies in aged mice and mice with doxorubicin-induced senescence.

Main Results:

• Proteins in the YAP-TEAD pathway were found to influence senescent cell viability.
• Verteporfin (VPF) selectively induced apoptosis in senescent cells by inhibiting the YAP-TEAD pathway, leading to DDIT4 upregulation and mTOR inhibition.
• Inhibition of mTOR reduced ER biogenesis, causing ER stress and apoptosis due to SASP demands.
• VPF treatment reduced senescent cell burden in aged and doxorubicin-treated mice.
• VPF improved tissue homeostasis in aging mouse lungs by reducing immune infiltration and TGF-β signaling.

Conclusions:

• The YAP-TEAD pathway is a viable target for senolytic therapy.
• Verteporfin (VPF) is an effective senolytic agent that eliminates senescent cells by inducing ER stress.
• Targeting ER activity required for SASP production offers a novel senolytic strategy.