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Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence.Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence.Fernández-Duran I, Quintanilla A, Tarrats N, Birch J, Hari P, Millar FR, Lagnado AB, Smer-Barreto V, Muir M, Brunton VG, Passos JF, Acosta JC.2021-12-15T23:00:00Z<h3>Abstract<br></h3><div><br></div><div>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.<br></div><p><a href="https://www.nature.com/articles/s41418-021-00917-6">Cell Death Differ</a>. 2021 Dec 16. (Epub ahead of print)<br></p>377

 
IBBTEC

Instituto de Biomedicina y Biotecnología de Cantabria.
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39011 Santander

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