Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: He, Yingli, She, Hua, Zhang, Ting, Xu, Haidong, Cheng, Lihong, Yepes, Manuel, Zhao, Yingren, Mao, Zixu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2018
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
_version_ 1783289502461067264
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
work_keys_str_mv AT heyingli p38mapkinhibitsautophagyandpromotesmicroglialinflammatoryresponsesbyphosphorylatingulk1
AT shehua p38mapkinhibitsautophagyandpromotesmicroglialinflammatoryresponsesbyphosphorylatingulk1
AT zhangting p38mapkinhibitsautophagyandpromotesmicroglialinflammatoryresponsesbyphosphorylatingulk1
AT xuhaidong p38mapkinhibitsautophagyandpromotesmicroglialinflammatoryresponsesbyphosphorylatingulk1
AT chenglihong p38mapkinhibitsautophagyandpromotesmicroglialinflammatoryresponsesbyphosphorylatingulk1
AT yepesmanuel p38mapkinhibitsautophagyandpromotesmicroglialinflammatoryresponsesbyphosphorylatingulk1
AT zhaoyingren p38mapkinhibitsautophagyandpromotesmicroglialinflammatoryresponsesbyphosphorylatingulk1
AT maozixu p38mapkinhibitsautophagyandpromotesmicroglialinflammatoryresponsesbyphosphorylatingulk1