Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-19935-y
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Funding
- National Key R&D Program of China [2016YFA0501900]
- China National Natural Science Foundation [31530041, 21837004, 91849204]
- Chinese Academy of Sciences [XDB39030000, XDB39030600]
- China National Natural Science Youth Foundation [31701210]
- Science and Technology Commission of Shanghai Municipality [18JC1420500]
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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, Ripk1(K612R/K612R) mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1(K612R/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 TNF alpha and pro-survival activity in response to TLRs signaling. RIPK1 is a critical kinase which mediates necroptosis, apoptosis and inflammation. Regulation of RIPK1 by ubiquitination is being intensively investigated. Here, the authors made knock-in RIPK1-K612R mice and demonstrate that this mutation alters the RIPK1 ubiquitinylation pattern and inhibits its prodeath kinase activity in response to TNF alpha but sensitizes cell death to TLRs signals.
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