The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK; Walter and Elisa Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia.
The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
Cell Rep. 2018 Apr 10;23(2):470-484. doi: 10.1016/j.celrep.2018.03.054.
Tumor necrosis factor (TNF) is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation. Although depletion of MIB2 has little effect on NF-κB activation, it sensitizes cells to RIPK1- and caspase-8-dependent cell death. We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. Disruption of MIB2-mediated ubiquitylation, either by mutation of MIB2's E3 activity or RIPK1's ubiquitin-acceptor lysines, sensitizes cells to RIPK1-mediated cell death. Together, our findings demonstrate that Mind Bomb E3 ubiquitin ligases can function as additional checkpoint of cytokine-induced cell death, selectively protecting cells from the cytotoxic effects of TNF.
肿瘤坏死因子 (TNF) 是一种炎症细胞因子，可以发出细胞存活或细胞死亡的信号。在这些不同结果之间切换的机制仍未得到很好的定义。在这里，我们表明 E3 泛素连接酶 Mind Bomb-2 (MIB2) 通过抑制泛素化使 RIPK1 失活来调节 TNF 诱导的细胞死亡。尽管 MIB2 的耗竭对 NF-κB 的激活几乎没有影响，但它会使细胞对 RIPK1 和 caspase-8 依赖性细胞死亡敏感。我们发现 MIB2 通过泛素化 RIPK1 的 C 末端部分的赖氨酸残基来抑制 RIPK1 的细胞毒性潜力。我们的数据表明，RIPK1 的泛素化修饰干扰了 RIPK1 寡聚化和 RIPK1-FADD 结合。通过突变 MIB2 的 E3 活性或 RIPK1 的泛素受体赖氨酸，破坏 MIB2 介导的泛素化会使细胞对 RIPK1 介导的细胞死亡敏感。总之，我们的研究结果表明，Mind Bomb E3 泛素连接酶可以作为细胞因子诱导的细胞死亡的额外检查点，选择性地保护细胞免受 TNF 的细胞毒性影响。
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