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PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote TNFα-mediated cell death

Activation of TNFR1 by TNFα induces the formation of a membrane-associated, intracellular complex termed complex I. Complex I orchestrates a complex pattern of modifications on key regulators of TNF signaling that collectively determines the cell fate by activating pro-survival or executing cell dea...

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Autores principales: Wu, Guowei, Li, Dekang, Liang, Wei, Sun, Weimin, Xie, Xingxing, Tong, Yilun, Shan, Bing, Zhang, Mengmeng, Lu, Xiaojuan, Yuan, Junying, Li, Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9452587/
https://www.ncbi.nlm.nih.gov/pubmed/36071040
http://dx.doi.org/10.1038/s41419-022-05206-9
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author Wu, Guowei
Li, Dekang
Liang, Wei
Sun, Weimin
Xie, Xingxing
Tong, Yilun
Shan, Bing
Zhang, Mengmeng
Lu, Xiaojuan
Yuan, Junying
Li, Ying
author_facet Wu, Guowei
Li, Dekang
Liang, Wei
Sun, Weimin
Xie, Xingxing
Tong, Yilun
Shan, Bing
Zhang, Mengmeng
Lu, Xiaojuan
Yuan, Junying
Li, Ying
author_sort Wu, Guowei
collection PubMed
description Activation of TNFR1 by TNFα induces the formation of a membrane-associated, intracellular complex termed complex I. Complex I orchestrates a complex pattern of modifications on key regulators of TNF signaling that collectively determines the cell fate by activating pro-survival or executing cell death programs. However, the regulatory mechanism of complex I in cell-fate decision is not fully understood. Here we identify protein phosphatase-6 (PP6) as a previously unidentified component of complex I. Loss of PP6 protects cells from TNFα-mediated cell death. The role of PP6 in regulating cell death requires its phosphatase activity and regulatory subunits. Further mechanistic studies show that PP6 modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote RIPK1 activation and c-FLIP(L) degradation. We also show that melanoma-associated PP6 inactivating mutants offer resistance to cell death due to the loss of sensitivity to TNFα. Thus, our study provides a potential mechanism by which melanoma-related PP6 inactivating mutations promote cancer progression.
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spelling pubmed-94525872022-09-09 PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote TNFα-mediated cell death Wu, Guowei Li, Dekang Liang, Wei Sun, Weimin Xie, Xingxing Tong, Yilun Shan, Bing Zhang, Mengmeng Lu, Xiaojuan Yuan, Junying Li, Ying Cell Death Dis Article Activation of TNFR1 by TNFα induces the formation of a membrane-associated, intracellular complex termed complex I. Complex I orchestrates a complex pattern of modifications on key regulators of TNF signaling that collectively determines the cell fate by activating pro-survival or executing cell death programs. However, the regulatory mechanism of complex I in cell-fate decision is not fully understood. Here we identify protein phosphatase-6 (PP6) as a previously unidentified component of complex I. Loss of PP6 protects cells from TNFα-mediated cell death. The role of PP6 in regulating cell death requires its phosphatase activity and regulatory subunits. Further mechanistic studies show that PP6 modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote RIPK1 activation and c-FLIP(L) degradation. We also show that melanoma-associated PP6 inactivating mutants offer resistance to cell death due to the loss of sensitivity to TNFα. Thus, our study provides a potential mechanism by which melanoma-related PP6 inactivating mutations promote cancer progression. Nature Publishing Group UK 2022-09-07 /pmc/articles/PMC9452587/ /pubmed/36071040 http://dx.doi.org/10.1038/s41419-022-05206-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wu, Guowei
Li, Dekang
Liang, Wei
Sun, Weimin
Xie, Xingxing
Tong, Yilun
Shan, Bing
Zhang, Mengmeng
Lu, Xiaojuan
Yuan, Junying
Li, Ying
PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote TNFα-mediated cell death
title PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote TNFα-mediated cell death
title_full PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote TNFα-mediated cell death
title_fullStr PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote TNFα-mediated cell death
title_full_unstemmed PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote TNFα-mediated cell death
title_short PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP(L) to promote TNFα-mediated cell death
title_sort pp6 negatively modulates lubac-mediated m1-ubiquitination of ripk1 and c-flip(l) to promote tnfα-mediated cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9452587/
https://www.ncbi.nlm.nih.gov/pubmed/36071040
http://dx.doi.org/10.1038/s41419-022-05206-9
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