Identification of a P62-TIF-IA axis that drives nucleolar fusion and the senescence associated secretory phenotype

Abstract

Two key characteristics of senescent cells are nucleolar fusion and secretion of a plethora of pro-inflammatory cytokines called the senescence-associated secretory phenotype (SASP). The SASP is dependent on NF-κB but the initial trigger, and links with nucleoli, are unclear. Using multiplein vitroandin vivomodels, we show that an early response to oncogene- and therapy-induced senescence (OIS and TIS) is nuclear/nucleolar accumulation of the PolI complex component, TIF-IA. This accumulation is essential for nucleolar fusion, the SASP and senescence, independent of rDNA transcription. We show that in steady state, TIF-IA is targeted for autophagic degradation by the p62 cargo receptor and that accumulation in senescence occurs as a consequence of ATM activation, which disrupts the p62-TIF-IA interaction. In mice, TIF-IA accumulates in colonic mucosa with age, which is further enhanced in thenfkb1-/-model of accelerated ageing. Together, these results reveal a p62-TIF-IA nucleolar stress axis that regulates the SASP and senescence, and that warrants further investigation as an anti-ageing target.