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m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response

N6-methyladenosine (m6A) is an abundant mRNA modification that affects multiple biological processes, including those involved in the cell stress response and viral infection. YTH domain family 2 (YTHDF2) is an m6A-binding protein that affects the localization and stability of targeted mRNA. RNA-bin...

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Autores principales: Yu, Ruiqing, Li, Qimeng, Feng, Zhihui, Cai, Luhui, Xu, Qiong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470741/
https://www.ncbi.nlm.nih.gov/pubmed/30875984
http://dx.doi.org/10.3390/ijms20061323
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author Yu, Ruiqing
Li, Qimeng
Feng, Zhihui
Cai, Luhui
Xu, Qiong
author_facet Yu, Ruiqing
Li, Qimeng
Feng, Zhihui
Cai, Luhui
Xu, Qiong
author_sort Yu, Ruiqing
collection PubMed
description N6-methyladenosine (m6A) is an abundant mRNA modification that affects multiple biological processes, including those involved in the cell stress response and viral infection. YTH domain family 2 (YTHDF2) is an m6A-binding protein that affects the localization and stability of targeted mRNA. RNA-binding proteins (RBPs) can regulate the stability of inflammatory gene mRNA transcripts, thus participating in the regulation of inflammatory processes. As an RBP, the role of YTHDF2 in the LPS-induced inflammatory reaction has not been reported. To elucidate the function of YTHDF2 in the inflammatory response of macrophages, we first detected the expression level of YTHDF2 in RAW 264.7 cells, and found that it was upregulated after LPS stimulation. YTHDF2 knockdown significantly increased the LPS-induced IL-6, TNF-α, IL-1β, and IL-12 expression and the phosphorylation of p65, p38, and ERK1/2 in NF-κB and MAPK signaling. Moreover, the upregulated expression of TNF-α and IL-6 in cells with silenced YTHDF2 expression was downregulated by the NF-κB, p38, and ERK inhibitors. YTHDF2 depletion increased the expression and stability of MAP2K4 and MAP4K4 mRNAs. All of these results suggest that YTHDF2 knockdown increases mRNA expression levels of MAP2K4 and MAP4K4 via stabilizing the mRNA transcripts, which activate MAPK and NF-κB signaling pathways, which promote the expression of proinflammatory cytokines and aggravate the inflammatory response in LPS-stimulated RAW 264.7 cells.
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spelling pubmed-64707412019-04-26 m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response Yu, Ruiqing Li, Qimeng Feng, Zhihui Cai, Luhui Xu, Qiong Int J Mol Sci Article N6-methyladenosine (m6A) is an abundant mRNA modification that affects multiple biological processes, including those involved in the cell stress response and viral infection. YTH domain family 2 (YTHDF2) is an m6A-binding protein that affects the localization and stability of targeted mRNA. RNA-binding proteins (RBPs) can regulate the stability of inflammatory gene mRNA transcripts, thus participating in the regulation of inflammatory processes. As an RBP, the role of YTHDF2 in the LPS-induced inflammatory reaction has not been reported. To elucidate the function of YTHDF2 in the inflammatory response of macrophages, we first detected the expression level of YTHDF2 in RAW 264.7 cells, and found that it was upregulated after LPS stimulation. YTHDF2 knockdown significantly increased the LPS-induced IL-6, TNF-α, IL-1β, and IL-12 expression and the phosphorylation of p65, p38, and ERK1/2 in NF-κB and MAPK signaling. Moreover, the upregulated expression of TNF-α and IL-6 in cells with silenced YTHDF2 expression was downregulated by the NF-κB, p38, and ERK inhibitors. YTHDF2 depletion increased the expression and stability of MAP2K4 and MAP4K4 mRNAs. All of these results suggest that YTHDF2 knockdown increases mRNA expression levels of MAP2K4 and MAP4K4 via stabilizing the mRNA transcripts, which activate MAPK and NF-κB signaling pathways, which promote the expression of proinflammatory cytokines and aggravate the inflammatory response in LPS-stimulated RAW 264.7 cells. MDPI 2019-03-15 /pmc/articles/PMC6470741/ /pubmed/30875984 http://dx.doi.org/10.3390/ijms20061323 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yu, Ruiqing
Li, Qimeng
Feng, Zhihui
Cai, Luhui
Xu, Qiong
m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response
title m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response
title_full m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response
title_fullStr m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response
title_full_unstemmed m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response
title_short m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response
title_sort m6a reader ythdf2 regulates lps-induced inflammatory response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470741/
https://www.ncbi.nlm.nih.gov/pubmed/30875984
http://dx.doi.org/10.3390/ijms20061323
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