Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence

Irene Fernández Duran, Andrea Quintanilla, Nuria Tarrats, Jodie Birch, Priya Hari, Fraser Millar, Anthony B. Lagnado, Vanessa Smer Barreto, Morwenna Muir, Valerie G Brunton, João F. Passos, Juan-Carlos Acosta*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Cytoplasmic recognition of microbial lipopolysaccharides (LPS) in human cells is elicited by the caspase-4 and caspase-5 noncanonical inflammasomes, which induce a form of inflammatory cell death termed pyroptosis. Here we show that LPS-mediated activation of caspase-4 also induces a stress response promoting cellular senescence, which is dependent on the caspase-4 substrate gasdermin-D and the tumor suppressor p53. Furthermore, we found that the caspase-4 noncanonical inflammasome is induced and assembled in response to oncogenic RAS signaling during oncogene-induced senescence (OIS). Moreover, targeting caspase-4 expression in OIS showed its critical role in the senescence-associated secretory phenotype and the cell cycle arrest induced in cellular senescence. Finally, we observed that caspase-4 induction occurs in vivo in mouse models of tumor suppression and ageing. Altogether, we are showing that cellular senescence is induced by cytoplasmic LPS recognition by the noncanonical inflammasome and that this pathway is conserved in the cellular response to oncogenic stress.
Original languageEnglish
JournalCell Death & Differentiation (CDD)
Early online date16 Dec 2021
Publication statusE-pub ahead of print - 16 Dec 2021


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