Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners

Xingyan Li, Mengmeng Zhang, Xinyue Huang, Wei Liang, Ganquan Li, Xiaojuan Lu, Yanxia Li, Heling Pan, Linyu Shi, Hong Zhu, Lihui Qian, Bing Shan () and Junying Yuan ()
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Xingyan Li: Chinese Academy of Sciences
Mengmeng Zhang: Chinese Academy of Sciences
Xinyue Huang: Chinese Academy of Sciences
Wei Liang: Chinese Academy of Sciences
Ganquan Li: Chinese Academy of Sciences
Xiaojuan Lu: Chinese Academy of Sciences
Yanxia Li: Chinese Academy of Sciences
Heling Pan: Chinese Academy of Sciences
Linyu Shi: Chinese Academy of Sciences
Hong Zhu: Harvard Medical School
Lihui Qian: Chinese Academy of Sciences
Bing Shan: Chinese Academy of Sciences
Junying Yuan: Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract 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/K612R mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1K612R/K612R mice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially by Ripk3 deficiency. 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.

Date: 2020
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DOI: 10.1038/s41467-020-19935-y

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