The Senescence-Associated Secretory Phenotype constitutes HIF-1α activation but is independent of micronuclei-induced cGas/Sting activation

Abstract

The Senescence-Associated Secretory Phenotype (SASP), characterized by the upregulation of inflammatory cytokines, is triggered during senescence by anti-proliferation stresses, including replicative exhaustion, {gamma}-irradiation, Ras oncogene induction, and centrosome amplification. The elucidation of common signalling pathway(s) activated in SASP, induced by different anti-proliferation stresses, remains an important question. Indeed, micronuclei activation of the cGAS/Sting pathway, which has been thought to drive SASP(Kwon, Leibowitz, and Lee, 2020), remains controversial(Flynn, Koch, and Mitchison, 2021; Sato and Hayashi, 2024; Takaki et al., 2024). In this report, analyses of various cell lines induced to undergo senescence by diverse stressors revealed that HIF-1 is specifically induced in senescence but not in quiescence. Consistent with our previous findings(Wu et al., 2023a), we have further demonstrated how centrosome amplification induces a non-canonical SASP dominated by HIF-1 activation rather than the classical NF{kappa}B signaling. Lastly, we revealed that during SASP, centrosome amplification-generated micronuclei do not activate the cGAS/Sting-mediated interferon response. Together, our findings demonstrate that HIF-1-activation in SASP is a defining feature of the SASP induced by diverse stressors, acting independently of micronuclei generation and cGAS/Sting activation.