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.
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DOI：
10.1038/s41418-021-00917-6
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发表时间：
2022-06
影响因子：
12.4
通讯作者：
Acosta, Juan Carlos
中科院分区：
文献类型：
--
作者：
Fernandez-Duran, Irene;Quintanilla, Andrea;Tarrats, Nuria;Birch, Jodie;Hari, Priya;Millar, Fraser R.;Lagnado, Anthony B.;Smer-Barreto, Vanessa;Muir, Morwenna;Brunton, Valerie G.;Passos, Joao F.;Acosta, Juan Carlos
Caspase-4和caspase-5的非规范性炎性小体可诱导一种称为炎性下垂的炎性细胞死亡，从而引起人体细胞对微生物脂多糖的胞质识别。在这里，我们表明，内毒素介导的caspase-4的激活也诱导了促进细胞衰老的应激反应，这依赖于caspase-4底物Gasdermin-D和肿瘤抑制因子P53。此外，我们还发现，在癌基因诱导的衰老(OIS)过程中，caspase-4非典型炎症体被诱导和组装，以响应致癌的RAS信号。此外，靶向Caspase-4在OIS中的表达显示其在衰老相关的分泌表型和诱导细胞衰老过程中的细胞周期停滞中起关键作用。最后，我们观察到，在肿瘤抑制和衰老的小鼠模型中，caspase-4的诱导发生在体内。综上所述，我们的研究表明，细胞衰老是由非典型炎症体对胞浆内毒素的识别引起的，并且这一途径在细胞对致癌应激的反应中是保守的。
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.
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影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
64.5
作者：
Kuilman, Thomas;Michaloglou, Chrysiis;Peeper, Daniel S.
通讯作者：
Peeper, Daniel S.
影响因子：
21.3
作者：
Glück S;Guey B;Gulen MF;Wolter K;Kang TW;Schmacke NA;Bridgeman A;Rehwinkel J;Zender L;Ablasser A
通讯作者：
Ablasser A
影响因子：
16.6
作者：
Jurk, Diana;Wilson, Caroline;Passos, Joao F.;Oakley, Fiona;Correia-Melo, Clara;Greaves, Laura;Saretzki, Gabriele;Fox, Chris;Lawless, Conor;Anderson, Rhys;Hewitt, Graeme;Pender, Sylvia L. F.;Fullard, Nicola;Nelson, Glyn;Mann, Jelena;van de Sluis, Bart;Mann, Derek A.;von Zglinicki, Thomas
通讯作者：
von Zglinicki, Thomas
影响因子：
64.8
作者：
Dou Z;Ghosh K;Vizioli MG;Zhu J;Sen P;Wangensteen KJ;Simithy J;Lan Y;Lin Y;Zhou Z;Capell BC;Xu C;Xu M;Kieckhaefer JE;Jiang T;Shoshkes-Carmel M;Tanim KMAA;Barber GN;Seykora JT;Millar SE;Kaestner KH;Garcia BA;Adams PD;Berger SL
通讯作者：
Berger SL