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

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 RIP...

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Autores principales: Li, Xingyan, Zhang, Mengmeng, Huang, Xinyue, Liang, Wei, Li, Ganquan, Lu, Xiaojuan, Li, Yanxia, Pan, Heling, Shi, Linyu, Zhu, Hong, Qian, Lihui, Shan, Bing, Yuan, Junying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733462/
https://www.ncbi.nlm.nih.gov/pubmed/33311474
http://dx.doi.org/10.1038/s41467-020-19935-y
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author Li, Xingyan
Zhang, Mengmeng
Huang, Xinyue
Liang, Wei
Li, Ganquan
Lu, Xiaojuan
Li, Yanxia
Pan, Heling
Shi, Linyu
Zhu, Hong
Qian, Lihui
Shan, Bing
Yuan, Junying
author_facet Li, Xingyan
Zhang, Mengmeng
Huang, Xinyue
Liang, Wei
Li, Ganquan
Lu, Xiaojuan
Li, Yanxia
Pan, Heling
Shi, Linyu
Zhu, Hong
Qian, Lihui
Shan, Bing
Yuan, Junying
author_sort Li, Xingyan
collection PubMed
description 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 TNFα and pro-survival activity in response to TLRs signaling.
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spelling pubmed-77334622020-12-17 Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners Li, Xingyan Zhang, Mengmeng Huang, Xinyue Liang, Wei Li, Ganquan Lu, Xiaojuan Li, Yanxia Pan, Heling Shi, Linyu Zhu, Hong Qian, Lihui Shan, Bing Yuan, Junying Nat Commun Article 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 TNFα and pro-survival activity in response to TLRs signaling. Nature Publishing Group UK 2020-12-11 /pmc/articles/PMC7733462/ /pubmed/33311474 http://dx.doi.org/10.1038/s41467-020-19935-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Li, Xingyan
Zhang, Mengmeng
Huang, Xinyue
Liang, Wei
Li, Ganquan
Lu, Xiaojuan
Li, Yanxia
Pan, Heling
Shi, Linyu
Zhu, Hong
Qian, Lihui
Shan, Bing
Yuan, Junying
Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
title Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
title_full Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
title_fullStr Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
title_full_unstemmed Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
title_short Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
title_sort ubiquitination of ripk1 regulates its activation mediated by tnfr1 and tlrs signaling in distinct manners
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733462/
https://www.ncbi.nlm.nih.gov/pubmed/33311474
http://dx.doi.org/10.1038/s41467-020-19935-y
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