Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, UK.
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.
Cell Death Differ. 2022 Jun;29(6):1267-1282. doi: 10.1038/s41418-021-00917-6. Epub 2021 Dec 16.
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.
细胞质中对微生物脂多糖（LPS）的识别是由非经典的半胱天冬酶-4 和半胱天冬酶-5 炎性小体引起的，这会诱导一种称为细胞焦亡的炎症细胞死亡形式。在这里，我们表明 LPS 介导的半胱天冬酶-4 的激活也会诱导一种应激反应，促进细胞衰老，这依赖于半胱天冬酶-4 的底物 gasdermin-D 和肿瘤抑制因子 p53。此外，我们发现，在癌基因诱导的衰老（OIS）期间，半胱天冬酶-4 的非经典炎性小体是响应致癌 RAS 信号而被诱导和组装的。此外，靶向 OIS 中的半胱天冬酶-4 表达显示其在衰老相关分泌表型和细胞周期停滞中诱导细胞衰老中的关键作用。最后，我们观察到在肿瘤抑制和衰老的小鼠模型中体内诱导了半胱天冬酶-4 的诱导。总之，我们证明了细胞质中 LPS 通过非经典炎性小体的识别诱导了细胞衰老，并且该途径在细胞对致癌应激的反应中是保守的。
