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PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation

Receptor interaction protein kinase 1 (RIPK1) plays a diverse role in tumor necrosis factor α (TNFα) signalings. The ubiquitination of RIPK1 is essential for NF-κB activation, whereas its kinase activity promotes apoptosis and necroptosis. However, the mechanisms underlying have not been fully illum...

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Autores principales: Zhou, Chenchen, Zhang, Xueli, Yang, Cuiping, He, Yuan, Zhang, Luo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285381/
https://www.ncbi.nlm.nih.gov/pubmed/34272357
http://dx.doi.org/10.1038/s41419-021-04001-2
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author Zhou, Chenchen
Zhang, Xueli
Yang, Cuiping
He, Yuan
Zhang, Luo
author_facet Zhou, Chenchen
Zhang, Xueli
Yang, Cuiping
He, Yuan
Zhang, Luo
author_sort Zhou, Chenchen
collection PubMed
description Receptor interaction protein kinase 1 (RIPK1) plays a diverse role in tumor necrosis factor α (TNFα) signalings. The ubiquitination of RIPK1 is essential for NF-κB activation, whereas its kinase activity promotes apoptosis and necroptosis. However, the mechanisms underlying have not been fully illuminated. Here we report that PH domain-containing family O member 2 (PLEKHO2) inhibits RIPK1-dependent cell death and is necessary for NF-κB activation in response to TNFα. Cells of PLKEHO2 deficiency are more susceptible to TNF-α induced apoptosis and necroptosis with increased RIPK1 activation, which is consistent with the observation that the susceptibility of PLEKHO2−/− cells is effectively prevented by treatment of RIPK1 kinase inhibitor. Moreover, PLEKHO2 deficient cells exhibit compromised RIPK1 ubiquitination and NF-κB activation in response to TNFα. Ultimately, PLEKHO2-deficient mice display greatly increased hepatotoxicity and lethality after TNFα-induced hepatitis. In summary, our study revealed that PLEKHO2 is a novel inhibitor of apoptosis and necroptosis, which plays a key role in regulating RIPK1 ubiquitination and activation
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spelling pubmed-82853812021-07-23 PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation Zhou, Chenchen Zhang, Xueli Yang, Cuiping He, Yuan Zhang, Luo Cell Death Dis Article Receptor interaction protein kinase 1 (RIPK1) plays a diverse role in tumor necrosis factor α (TNFα) signalings. The ubiquitination of RIPK1 is essential for NF-κB activation, whereas its kinase activity promotes apoptosis and necroptosis. However, the mechanisms underlying have not been fully illuminated. Here we report that PH domain-containing family O member 2 (PLEKHO2) inhibits RIPK1-dependent cell death and is necessary for NF-κB activation in response to TNFα. Cells of PLKEHO2 deficiency are more susceptible to TNF-α induced apoptosis and necroptosis with increased RIPK1 activation, which is consistent with the observation that the susceptibility of PLEKHO2−/− cells is effectively prevented by treatment of RIPK1 kinase inhibitor. Moreover, PLEKHO2 deficient cells exhibit compromised RIPK1 ubiquitination and NF-κB activation in response to TNFα. Ultimately, PLEKHO2-deficient mice display greatly increased hepatotoxicity and lethality after TNFα-induced hepatitis. In summary, our study revealed that PLEKHO2 is a novel inhibitor of apoptosis and necroptosis, which plays a key role in regulating RIPK1 ubiquitination and activation Nature Publishing Group UK 2021-07-16 /pmc/articles/PMC8285381/ /pubmed/34272357 http://dx.doi.org/10.1038/s41419-021-04001-2 Text en © The Author(s) 2021 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
Zhou, Chenchen
Zhang, Xueli
Yang, Cuiping
He, Yuan
Zhang, Luo
PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation
title PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation
title_full PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation
title_fullStr PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation
title_full_unstemmed PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation
title_short PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation
title_sort plekho2 inhibits tnfα-induced cell death by suppressing ripk1 activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285381/
https://www.ncbi.nlm.nih.gov/pubmed/34272357
http://dx.doi.org/10.1038/s41419-021-04001-2
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