Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners.
Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners.
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RIPK1 泛素化以不同方式调节 TNFR1 和 TLR 信号转导介导的激活
DOI：
10.1038/s41467-020-19935-y
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发表时间：
2020-12-11
影响因子：
16.6
通讯作者：
Yuan J
中科院分区：
文献类型：
--
作者：
Li X;Zhang M;Huang X;Liang W;Li G;Lu X;Li Y;Pan H;Shi L;Zhu H;Qian L;Shan B;Yuan J
RIPK 1是一种含有死亡结构域（DD）的激酶，参与调节细胞凋亡、坏死性凋亡和炎症。已知RIPK 1的激活受DD介导的相互作用和泛素化的调控，但其潜在机制仍不完全清楚。在这里，我们表明，K627在人类RIPK 1-DD和其等效K612在小鼠RIPK 1-DD是一个关键的泛素化位点，调节RIPK 1的整体泛素化模式和DD介导的相互作用与其他DD含蛋白。K627 R/K612 R突变抑制RIPK 1的激活，并阻断TNFR 1信号转导介导的凋亡和坏死性凋亡。然而，Ripk 1 K612 R/K612 R突变使细胞对坏死性凋亡和caspase-1激活敏感，从而响应TLR信号。Ripk 1 K612 R/K612 R小鼠存活，但出现年龄依赖性的RIPK 1表达减少、自发性肠道炎症和脾肿大，这些可通过抗生素治疗和部分Ripk 3缺陷来挽救。此外，我们发现RIPK 1与FADD的相互作用有助于抑制TLR信号介导的RIPK 3的激活。我们的研究证实了K612泛素化在mRIPK 1/K627泛素化在hRIPK 1中调节其响应于TNFα的促死亡激酶活性和响应于TLR信号传导的促存活活性的不同作用。
RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to be regulated by its DD-mediated interaction and ubiquitination, though underlying mechanisms remain incompletely understood. Here we show that K627 in human RIPK1-DD and its equivalent K612 in murine RIPK1-DD is a key ubiquitination site that regulates the overall ubiquitination pattern of RIPK1 and its DD-mediated interactions with other DD-containing proteins. K627R/K612R mutation inhibits the activation of RIPK1 and blocks both apoptosis and necroptosis mediated by TNFR1 signaling. However,Ripk1K612R/K612Rmutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling.Ripk1K612R/K612Rmice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially byRipk3deficiency. Furthermore, we show that the interaction of RIPK1 with FADD contributes to suppressing the activation of RIPK3 mediated by TLRs signaling. Our study demonstrates the distinct roles of K612 ubiquitination in mRIPK1/K627 ubiquitination in hRIPK1 in regulating its pro-death kinase activity in response to TNFα and pro-survival activity in response to TLRs signaling.
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影响因子：
4.8
作者：
Kaiser, William J.;Sridharan, Haripriya;Mocarski, Edward S.
通讯作者：
Mocarski, Edward S.
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.
影响因子：
16
作者：
Ea, CK;Deng, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
通过TAK1介导的磷酸化来调节RIPK1激活，决定了凋亡和坏死性。
影响因子：
16.6
作者：
Geng J;Ito Y;Shi L;Amin P;Chu J;Ouchida AT;Mookhtiar AK;Zhao H;Xu D;Shan B;Najafov A;Gao G;Akira S;Yuan J
通讯作者：
Yuan J
DOI：
10.1073/pnas.1813582116
发表时间：
2019-01-15
影响因子：
11.1
作者：
Li, Yue;Fuehrer, Marita;Kotlarz, Daniel
通讯作者：
Kotlarz, Daniel