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

Abstract

Cytoplasmic recognition of microbially derived lipopolysaccharides (LPS) in human cells is elicited by the inflammatory cysteine aspartic proteases caspase-4 and caspase-5, which activate non-canonical inflammasomes inducing a form of inflammatory programmed cell death termed pyroptosis. Here we show that LPS mediated activation of the non-canonical inflammasome also induces cellular senescence and the activation of tumour suppressor stress responses in human diploid fibroblasts. Interestingly, this LPS-induced senescence is dependent on caspase-4, the pyroptotic effector protein gasdermin-D and the tumour suppressor protein p53. Also, experiments with a catalytically deficient mutant suggest that caspase-4 proteolytic activity is not necessary for its role in senescence. Furthermore, we found that the caspase-4 non-canonical inflammasome is induced and assembled during Ras-mediated oncogene-induced senescence (OIS). Moreover, targeting caspase-4 in OIS showed that the non-canonical inflammasome is critical for SASP activation and contributes to reinforcing the cell cycle arrest in OIS. Finally, we observed that caspase-4 induction occurs in vivo in models of tumour suppression and ageing. Altogether, we are unveiling that cellular senescence is induced by cytoplasmic microbial LPS recognition by the caspase-4 non-canonical inflammasome and that this pathway is conserved in the senescence program induced by oncogenic stress.