TY - JOUR
T1 - Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence
AU - Fernández-Duran, Irene
AU - Quintanilla, Andrea
AU - Tarrats, Núria
AU - Birch, Jodie
AU - Hari, Priya
AU - Millar, Fraser R.
AU - Lagnado, Anthony B.
AU - Smer-Barreto, Vanessa
AU - Muir, Morwenna
AU - Brunton, Valerie G.
AU - Passos, João F.
AU - Acosta, Juan Carlos
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85121452166&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85121452166&partnerID=8YFLogxK
U2 - 10.1038/s41418-021-00917-6
DO - 10.1038/s41418-021-00917-6
M3 - Article
C2 - 34916628
AN - SCOPUS:85121452166
SN - 1350-9047
VL - 29
SP - 1267
EP - 1282
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 6
ER -