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p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1
Inflammation and autophagy are two critical cellular processes. The relationship between these two processes is complex and includes the suppression of inflammation by autophagy. However, the signaling mechanisms that relieve this autophagy-mediated inhibition of inflammation to permit a beneficial...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748971/ https://www.ncbi.nlm.nih.gov/pubmed/29196462 http://dx.doi.org/10.1083/jcb.201701049 |
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author | He, Yingli She, Hua Zhang, Ting Xu, Haidong Cheng, Lihong Yepes, Manuel Zhao, Yingren Mao, Zixu |
author_facet | He, Yingli She, Hua Zhang, Ting Xu, Haidong Cheng, Lihong Yepes, Manuel Zhao, Yingren Mao, Zixu |
author_sort | He, Yingli |
collection | PubMed |
description | Inflammation and autophagy are two critical cellular processes. The relationship between these two processes is complex and includes the suppression of inflammation by autophagy. However, the signaling mechanisms that relieve this autophagy-mediated inhibition of inflammation to permit a beneficial inflammatory response remain unknown. We find that LPS triggers p38α mitogen-activated protein kinase (MAPK)–dependent phosphorylation of ULK1 in microglial cells. This phosphorylation inhibited ULK1 kinase activity, preventing it from binding to the downstream effector ATG13, and reduced autophagy in microglia. Consistently, p38α MAPK activity is required for LPS-induced morphological changes and the production of IL-1β by primary microglia in vitro and in the brain, which correlates with the p38α MAPK-dependent inhibition of autophagy. Furthermore, inhibition of ULK1 alone was sufficient to promote an inflammatory response in the absence of any overt inflammatory stimulation. Thus, our study reveals a molecular mechanism that enables the initial TLR4-triggered signaling pathway to inhibit autophagy and optimize inflammatory responses, providing new understanding into the mechanistic basis of the neuroinflammatory process. |
format | Online Article Text |
id | pubmed-5748971 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-57489712018-07-02 p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1 He, Yingli She, Hua Zhang, Ting Xu, Haidong Cheng, Lihong Yepes, Manuel Zhao, Yingren Mao, Zixu J Cell Biol Research Articles Inflammation and autophagy are two critical cellular processes. The relationship between these two processes is complex and includes the suppression of inflammation by autophagy. However, the signaling mechanisms that relieve this autophagy-mediated inhibition of inflammation to permit a beneficial inflammatory response remain unknown. We find that LPS triggers p38α mitogen-activated protein kinase (MAPK)–dependent phosphorylation of ULK1 in microglial cells. This phosphorylation inhibited ULK1 kinase activity, preventing it from binding to the downstream effector ATG13, and reduced autophagy in microglia. Consistently, p38α MAPK activity is required for LPS-induced morphological changes and the production of IL-1β by primary microglia in vitro and in the brain, which correlates with the p38α MAPK-dependent inhibition of autophagy. Furthermore, inhibition of ULK1 alone was sufficient to promote an inflammatory response in the absence of any overt inflammatory stimulation. Thus, our study reveals a molecular mechanism that enables the initial TLR4-triggered signaling pathway to inhibit autophagy and optimize inflammatory responses, providing new understanding into the mechanistic basis of the neuroinflammatory process. The Rockefeller University Press 2018-01-02 /pmc/articles/PMC5748971/ /pubmed/29196462 http://dx.doi.org/10.1083/jcb.201701049 Text en © 2018 He et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles He, Yingli She, Hua Zhang, Ting Xu, Haidong Cheng, Lihong Yepes, Manuel Zhao, Yingren Mao, Zixu p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1 |
title | p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1 |
title_full | p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1 |
title_fullStr | p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1 |
title_full_unstemmed | p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1 |
title_short | p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1 |
title_sort | p38 mapk inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ulk1 |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748971/ https://www.ncbi.nlm.nih.gov/pubmed/29196462 http://dx.doi.org/10.1083/jcb.201701049 |
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