Transglutaminase 2 mediates the p53-dependent senescence-associated secretory phenotype

Senescent cells secrete a variety of NF-κB-dependent proteins, collectively known as the senescence-associated secretory phenotype (SASP), which promotes paracrine senescence, resistance to apoptosis, and chronic sterile inflammation. To clarify the role of SASP in both tumorigenesis and age-related diseases, we investigated the mechanism underlying NF-κB activation in senescent cells. Here, we demonstrate that transglutaminase 2 (TG2) functions as an effector enzyme that activates NF-κB in response to DNA damage-induced stress. In normal cells, senescence inducers upregulated TG2 expression in a p53-dependent manner, thereby enhancing SASP. In contrast, in p53-inactivated cells, senescence inducers further elevated TG2 expression through a positive feedback loop, accounting for the paradoxical increase in SASP. Both TG2 knockdown and pharmacological inhibition reduced SASP. Moreover, TG2 promoted apoptotic resistance in senescent cells by inhibiting caspase-3 activity. Consistently, TG2-deficient mice exhibited reduced Ras-induced cytokine production and inflammation, while tissue-specific TG2 expression increased with age. Collectively, these findings identify TG2 as a key regulator of SASP and suggest its contribution to age-related pathologies.