The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
Mol Cell. 2018 Feb 15;69(4):566-580.e5. doi: 10.1016/j.molcel.2018.01.027.
Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation. We find that the ubiquitin-associated (UBA) domain of cellular inhibitor of apoptosis (cIAP)1 is required for optimal ubiquitin-lysine occupancy and K48 ubiquitylation of RIPK1. Independently of IKK and MK2, cIAP1-mediated and UBA-assisted ubiquitylation suppresses RIPK1 kinase auto-activation and, in addition, marks it for proteasomal degradation. In the absence of a functional UBA domain of cIAP1, more active RIPK1 kinase accumulates in response to TNF, causing RIPK1 kinase-mediated cell death and systemic inflammatory response syndrome. These results reveal a direct role for cIAP-mediated ubiquitylation in controlling RIPK1 kinase activity and preventing TNF-mediated cytotoxicity.
肿瘤坏死因子 (TNF) 可驱动炎症、细胞存活和死亡。虽然泛素化、磷酸化和核因子 κB (NF-κB) 依赖性检查点抑制 TNF 的细胞毒性潜力，但尚不清楚泛素化是否可以直接抑制 TNF 诱导的死亡。在这里，我们表明泛素化不仅通过激活下游激酶和 NF-κB 转录反应来调节 RIPK1 的细胞毒性潜力，而且还通过泛素依赖性失活直接抑制 RIPK1 激酶活性。我们发现细胞凋亡抑制剂 (cIAP)1 的泛素相关 (UBA) 结构域对于 RIPK1 的最佳泛素-赖氨酸占据和 K48 泛素化是必需的。独立于 IKK 和 MK2，cIAP1 介导的和 UBA 辅助的泛素化抑制 RIPK1 激酶的自动激活，并且还将其标记为蛋白酶体降解。在 cIAP1 的功能性 UBA 结构域缺失的情况下，更多的活性 RIPK1 激酶会积聚以响应 TNF，导致 RIPK1 激酶介导的细胞死亡和全身炎症反应综合征。这些结果揭示了 cIAP 介导的泛素化在控制 RIPK1 激酶活性和防止 TNF 介导的细胞毒性中的直接作用。
