The senescence-associated secretory phenotype constitutes HIF-1α activation but is independent of micronuclei-induced cGAS/STING activation

The Senescence-Associated Secretory Phenotype (SASP), characterized by the up-regulation of inflammatory cytokines, is triggered during senescence by antiproliferation stresses, including replicative exhaustion, γ-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, remains controversial. In this report, analyses of various cell lines induced to undergo senescence by diverse stressors revealed that HIF-1α is specifically induced in senescence but not in quiescence. Consistent with our previous findings, we have further demonstrated how centrosome amplification induces a noncanonical SASP dominated by HIF-1α activation rather than the classical NFκB signaling. Finally, we revealed that during SASP, centrosome amplification-generated micronuclei do not activate the cGAS/STING-mediated interferon response. Our conclusion is consistent with recent reports, with a more rigorous focus on the analysis of individual cells, indicating that micronuclei from chromosome missegregation fail to activate cGAS/STING-mediated innate immune response. Together, our findings demonstrate that HIF-1α-activation in SASP is a defining feature of the SASP induced by diverse stressors, acting independently of micronuclei generation and cGAS/STING activation.