L929 细胞中 TNF 诱导的坏死性凋亡受多个 TNFR1 复合物 I 和 II 成员的严格调控。,Cell Death & Disease

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L929 细胞中 TNF 诱导的坏死性凋亡受多个 TNFR1 复合物 I 和 II 成员的严格调控。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2011-Nov-17 , DOI: 10.1038/cddis.2011.111
N Vanlangenakker ₁ , M J M Bertrand , P Bogaert , P Vandenabeele , T Vanden Berghe

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TNF 受体 1 信号在 L929 细胞中诱导 NF-κB 活化和坏死性凋亡。我们之前报道了细胞凋亡蛋白介导的受体相互作用蛋白 1 (RIP1) 泛素化抑制剂作为细胞保护机制，而圆柱瘤病是一种 RIP1 去泛素化酶，可防止肿瘤坏死因子 (TNF) 诱导的坏死性凋亡。我们在此报告 RIP1 是 L929 细胞中经典 NF-κB 激活的关键介质，因此质疑 RIP1 泛素化与经典 NF-κB 激活的相对细胞保护作用。我们发现减弱的 NF-κB 激活对 TNF 诱导的坏死性凋亡没有影响。然而，我们发现 A20 和线性泛素链组装复合物是坏死性凋亡的负调节因子。出乎意料的是，与 RIP3 相比，我们还发现 RIP1 的敲低不会阻止 TNF 细胞毒性。细胞死亡分型显示 RIP1 耗尽的细胞从坏死性凋亡转变为凋亡性死亡，表明 RIP1 还可以抑制 L929 细胞的凋亡。相反，我们观察到 Fas 相关蛋白通过死亡域、细胞 FLICE 抑制蛋白和 caspase-8，它们都参与细胞凋亡的启动，抵消了坏死性凋亡的诱导。最后，我们还报告了在特定条件下 TNF 信号传导背景下 RIP1 独立但 RIP3 介导的坏死性凋亡。细胞 FLICE 抑制蛋白和 caspase-8 都参与了细胞凋亡的启动，抵消了坏死性凋亡的诱导。最后，我们还报告了在特定条件下 TNF 信号传导背景下 RIP1 独立但 RIP3 介导的坏死性凋亡。细胞 FLICE 抑制蛋白和 caspase-8 都参与了细胞凋亡的启动，抵消了坏死性凋亡的诱导。最后，我们还报告了在特定条件下 TNF 信号传导背景下 RIP1 独立但 RIP3 介导的坏死性凋亡。

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TNF-induced necroptosis in L929 cells is tightly regulated by multiple TNFR1 complex I and II members.

TNF receptor 1 signaling induces NF-κB activation and necroptosis in L929 cells. We previously reported that cellular inhibitor of apoptosis protein-mediated receptor-interacting protein 1 (RIP1) ubiquitination acts as a cytoprotective mechanism, whereas knockdown of cylindromatosis, a RIP1-deubiquitinating enzyme, protects against tumor necrosis factor (TNF)-induced necroptosis. We report here that RIP1 is a crucial mediator of canonical NF-κB activation in L929 cells, therefore questioning the relative cytoprotective contribution of RIP1 ubiquitination versus canonical NF-κB activation. We found that attenuated NF-κB activation has no impact on TNF-induced necroptosis. However, we identified A20 and linear ubiquitin chain assembly complex as negative regulators of necroptosis. Unexpectedly, and in contrast to RIP3, we also found that knockdown of RIP1 did not block TNF cytotoxicity. Cell death typing revealed that RIP1-depleted cells switch from necroptotic to apoptotic death, indicating that RIP1 can also suppress apoptosis in L929 cells. Inversely, we observed that Fas-associated protein via a death domain, cellular FLICE inhibitory protein and caspase-8, which are all involved in the initiation of apoptosis, counteract necroptosis induction. Finally, we also report RIP1-independent but RIP3-mediated necroptosis in the context of TNF signaling in particular conditions.

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