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Promyelocytic leukemia protein targets MK2 to promote cytotoxicity
Promyelocytic leukemia protein (PML) is a tumor suppressor possessing multiple modes of action, including induction of apoptosis. We unexpectedly find that PML promotes necroptosis in addition to apoptosis, with Pml (−/−) macrophages being more resistant to TNF‐mediated necroptosis than wild‐type co...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8647022/ https://www.ncbi.nlm.nih.gov/pubmed/34633746 http://dx.doi.org/10.15252/embr.202052254 |
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author | Chen, I‐Ting Chen, Hsiao‐Chi Lo, Yu‐Hsun Lai, Peng‐Yeh Hsieh, Fu‐Yi Wu, Yung‐Hsuan Shih, Hsiu‐Ming Lai, Ming‐Zong |
author_facet | Chen, I‐Ting Chen, Hsiao‐Chi Lo, Yu‐Hsun Lai, Peng‐Yeh Hsieh, Fu‐Yi Wu, Yung‐Hsuan Shih, Hsiu‐Ming Lai, Ming‐Zong |
author_sort | Chen, I‐Ting |
collection | PubMed |
description | Promyelocytic leukemia protein (PML) is a tumor suppressor possessing multiple modes of action, including induction of apoptosis. We unexpectedly find that PML promotes necroptosis in addition to apoptosis, with Pml (−/−) macrophages being more resistant to TNF‐mediated necroptosis than wild‐type counterparts and PML‐deficient mice displaying resistance to TNF‐induced systemic inflammatory response syndrome. Reduced necroptosis in PML‐deficient cells is associated with attenuated receptor‐interacting protein kinase 1 (RIPK1) activation, as revealed by reduced RIPK1[S166] phosphorylation, and attenuated RIPK1‐RIPK3‐MLKL necrosome complex formation. We show that PML deficiency leads to enhanced TNF‐induced MAPK‐activated kinase 2 (MK2) activation and elevated RIPK1[S321] phosphorylation, which suppresses necrosome formation. MK2 inhibitor treatment or MK2 knockout abrogates resistance to cell death induction in PML‐null cells and mice. PML binds MK2 and p38 MAPK, thereby inhibiting p38‐MK2 interaction and MK2 activation. Moreover, PML participates in autocrine production of TNF induced by cellular inhibitors of apoptosis 1 (cIAP1)/cIAP2 degradation, since PML‐knockout attenuates autocrine TNF. Thus, by targeting MK2 activation and autocrine TNF, PML promotes necroptosis and apoptosis, representing a novel tumor‐suppressive activity for PML. |
format | Online Article Text |
id | pubmed-8647022 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86470222021-12-20 Promyelocytic leukemia protein targets MK2 to promote cytotoxicity Chen, I‐Ting Chen, Hsiao‐Chi Lo, Yu‐Hsun Lai, Peng‐Yeh Hsieh, Fu‐Yi Wu, Yung‐Hsuan Shih, Hsiu‐Ming Lai, Ming‐Zong EMBO Rep Articles Promyelocytic leukemia protein (PML) is a tumor suppressor possessing multiple modes of action, including induction of apoptosis. We unexpectedly find that PML promotes necroptosis in addition to apoptosis, with Pml (−/−) macrophages being more resistant to TNF‐mediated necroptosis than wild‐type counterparts and PML‐deficient mice displaying resistance to TNF‐induced systemic inflammatory response syndrome. Reduced necroptosis in PML‐deficient cells is associated with attenuated receptor‐interacting protein kinase 1 (RIPK1) activation, as revealed by reduced RIPK1[S166] phosphorylation, and attenuated RIPK1‐RIPK3‐MLKL necrosome complex formation. We show that PML deficiency leads to enhanced TNF‐induced MAPK‐activated kinase 2 (MK2) activation and elevated RIPK1[S321] phosphorylation, which suppresses necrosome formation. MK2 inhibitor treatment or MK2 knockout abrogates resistance to cell death induction in PML‐null cells and mice. PML binds MK2 and p38 MAPK, thereby inhibiting p38‐MK2 interaction and MK2 activation. Moreover, PML participates in autocrine production of TNF induced by cellular inhibitors of apoptosis 1 (cIAP1)/cIAP2 degradation, since PML‐knockout attenuates autocrine TNF. Thus, by targeting MK2 activation and autocrine TNF, PML promotes necroptosis and apoptosis, representing a novel tumor‐suppressive activity for PML. John Wiley and Sons Inc. 2021-10-11 2021-12-06 /pmc/articles/PMC8647022/ /pubmed/34633746 http://dx.doi.org/10.15252/embr.202052254 Text en © 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Articles Chen, I‐Ting Chen, Hsiao‐Chi Lo, Yu‐Hsun Lai, Peng‐Yeh Hsieh, Fu‐Yi Wu, Yung‐Hsuan Shih, Hsiu‐Ming Lai, Ming‐Zong Promyelocytic leukemia protein targets MK2 to promote cytotoxicity |
title | Promyelocytic leukemia protein targets MK2 to promote cytotoxicity |
title_full | Promyelocytic leukemia protein targets MK2 to promote cytotoxicity |
title_fullStr | Promyelocytic leukemia protein targets MK2 to promote cytotoxicity |
title_full_unstemmed | Promyelocytic leukemia protein targets MK2 to promote cytotoxicity |
title_short | Promyelocytic leukemia protein targets MK2 to promote cytotoxicity |
title_sort | promyelocytic leukemia protein targets mk2 to promote cytotoxicity |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8647022/ https://www.ncbi.nlm.nih.gov/pubmed/34633746 http://dx.doi.org/10.15252/embr.202052254 |
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