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.

中文翻译：

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半胱氨酸天冬氨酸蛋白酶4非典型的炎性小体的细胞质先天免疫感应促进细胞衰老。

炎性半胱氨酸天冬氨酸蛋白酶caspase-4和caspase-5激发了人类细胞中微生物衍生的脂多糖（LPS）的细胞质识别，它们激活了非规范性炎症小体，诱导了某种形式的炎症性程序性细胞死亡，称为焦磷酸化。在这里，我们显示LPS介导的非规范性炎症小体的激活还诱导细胞衰老和人类二倍体成纤维细胞中肿瘤抑制应激反应的激活。有趣的是，这种LPS诱导的衰老取决于caspase-4，焦磷酸化效应蛋白gasdermin-D和肿瘤抑制蛋白p53。同样，使用催化缺陷型突变体的实验表明，caspase-4蛋白水解活性对于其在衰老中的作用不是必需的。此外，我们发现，在Ras介导的致癌基因诱导的衰老（OIS）过程中，诱导并组装了caspase-4非规范性炎症小体。此外，在OIS中靶向caspase-4的研究表明，非典型炎症小体对于SASP激活至关重要，并有助于加强OIS中的细胞周期停滞。最后，我们观察到在肿瘤抑制和衰老模型中体内发生caspase-4诱导。总而言之，我们揭示了细胞衰老是由胞质微生物LPS识别的caspase-4非经典炎症小体诱导的，该途径在致癌应激诱导的衰老程序中是保守的。在OIS中靶向caspase-4的研究表明，非典型炎症小体对于SASP活化至关重要，并有助于加强OIS中的细胞周期停滞。最后，我们观察到在肿瘤抑制和衰老模型中体内发生caspase-4诱导。总而言之，我们揭示了细胞衰老是由胞质微生物LPS识别的caspase-4非经典炎症小体诱导的，该途径在致癌应激诱导的衰老程序中是保守的。在OIS中靶向caspase-4的研究表明，非典型炎症小体对于SASP活化至关重要，并有助于加强OIS中的细胞周期停滞。最后，我们观察到在肿瘤抑制和衰老模型中体内发生caspase-4诱导。总而言之，我们揭示了细胞衰老是由胞质微生物LPS识别的caspase-4非经典炎症小体诱导的，该途径在致癌应激诱导的衰老程序中是保守的。