Epitranscriptomic reader YTHDF2 regulates SEK1( MAP2K4 )-JNK-cJUN inflammatory signaling in astrocytes during neurotoxic stress.

Autor:	Malovic E; Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA., Ealy A; Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA.; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA., Miller C; Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA.; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA., Jang A; Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA.; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA., Hsu PJ; Department of Chemistry, University of Chicago, Chicago, IL, USA., Sarkar S; Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA., Rokad D; Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA., Goeser C; Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA., Hartman AK; Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA., Zhu A; Department of Chemistry, University of Chicago, Chicago, IL, USA., Palanisamy B; Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA., Zenitsky G; Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA.; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA., Jin H; Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA.; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA., Anantharam V; Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA.; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA., Kanthasamy A; Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA.; Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA.; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA., He C; Department of Chemistry, University of Chicago, Chicago, IL, USA., Kanthasamy AG; Parkinson's Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA.; Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA.; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA.; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 Jul 31; Vol. 27 (9), pp. 110619. Date of Electronic Publication: 2024 Jul 31 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.110619
Abstrakt:	As the most abundant glial cells in the central nervous system (CNS), astrocytes dynamically respond to neurotoxic stress, however, the key molecular regulators controlling the inflammatory status of these sentinels during neurotoxic stress are many and complex. Herein, we demonstrate that the m6A epitranscriptomic mRNA modification tightly regulates the pro-inflammatory functions of astrocytes. Specifically, the astrocytic neurotoxic stressor, manganese (Mn), downregulated the m6A reader YTHDF2 in human and mouse astrocyte cultures and in the mouse brain. Functionally, YTHDF2 knockdown augmented, while its overexpression dampened, the neurotoxic stress-induced proinflammatory response, suggesting YTHDF2 serves as a key upstream regulator of inflammatory responses in astrocytes. Mechanistically, YTHDF2 RIP-sequencing identified MAP2K4 ( MKK4; SEK1) mRNA as a YTHDF2 target influencing inflammatory signaling. Our target validation revealed that Mn-exposed astrocytes mediate proinflammatory responses by activating the phosphorylation of SEK1, JNK, and cJUN signaling. Collectively, YTHDF2 serves as a key upstream 'molecular switch' controlling SEK1( MAP2K4 )-JNK-cJUN proinflammatory signaling in astrocytes. Competing Interests: A.G.K. and V.A. have an equity interest in PK Biosciences Corporation and Probiome Therapeutics, located at the University of Georgia, GA. The terms of this arrangement have been reviewed and approved by the University of Georgia in accordance with their conflict-of-interest policies. No other authors have conflicts of interest. (© 2024 The Author(s).)
Databáze:	MEDLINE
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