Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.
Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.
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DOI：
10.1016/j.molcel.2018.01.027
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发表时间：
2018-02-15
期刊：
影响因子：
16
通讯作者：
Meier P
中科院分区：
文献类型：
--
作者：
Annibaldi A;Wicky John S;Vanden Berghe T;Swatek KN;Ruan J;Liccardi G;Bianchi K;Elliott PR;Choi SM;Van Coillie S;Bertin J;Wu H;Komander D;Vandenabeele P;Silke J;Meier P
肿瘤坏死因子（TNF）可以驱动炎症、细胞存活和死亡。虽然泛素化、磷酸化和核因子κB （NF-κB）依赖的检查点抑制TNF的细胞毒性潜能，但泛素化是否能直接抑制TNF诱导的死亡尚不清楚。在这里，我们发现泛素化调节RIPK1的细胞毒性潜能不仅通过激活下游激酶和NF-kB转录反应，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）结构域是RIPK1的最佳泛素赖氨酸占用和K48泛素化所必需的。独立于IKK和MK2， ciap1介导和uba辅助的泛素化抑制RIPK1激酶的自激活，此外，标志着它的蛋白酶体降解。在缺少cIAP1功能性UBA结构域的情况下，更活跃的RIPK1激酶在对TNF的反应中积累，导致RIPK1激酶介导的细胞死亡和全身性炎症反应综合征。这些结果揭示了ciap介导的泛素化在控制RIPK1激酶活性和预防tnf介导的细胞毒性中的直接作用。泛素化直接控制TNF信号传导中的RIPK1激酶活性，UBA依赖的RIPK1泛素化抑制其激酶活性和细胞死亡，UBA有助于RIPK1中泛素受体赖氨酸的最佳占用，UBA依赖的RIPK1泛素化也将其靶向于蛋白酶体降解，Annibaldi等人表明，ciap介导的RIPK1激酶泛素化抑制其自身激活，此外，还标志着它的蛋白酶体降解。这些结果揭示了泛素在控制RIPK1激酶活性和抑制tnf介导的细胞毒性中的直接作用。
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. Ubiquitylation directly controls RIPK1 kinase activity in TNF signaling UBA-dependent ubiquitylation of RIPK1 represses its kinase activity and cell death The UBA contributes to optimal occupancy of ubiquitin-acceptor lysines in RIPK1 UBA-dependent ubiquitylation of RIPK1 also targets it for proteasomal degradation Annibaldi et al. show that cIAP-mediated ubiquitylation of RIPK1 kinase suppresses its auto-activation and, in addition, marks it for proteasomal degradation. These results reveal a direct role for ubiquitin in controlling RIPK1 kinase activity and suppressing TNF-mediated cytotoxicity.
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DOI：
10.1007/s00018-016-2191-4
发表时间：
2016-06
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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影响因子：
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作者：
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