Epitranscriptomic reader YTHDF2 regulates SEK1(MAP2K4)-JNK-cJUN inflammatory signaling in astrocytes during neurotoxic stress
Emir Malovic,
Alyssa Ealy,
Cameron Miller,
Ahyoung Jang,
Phillip J. Hsu,
Souvarish Sarkar,
Dharmin Rokad,
Cody Goeser,
Aleah Kristen Hartman,
Allen Zhu,
Bharathi Palanisamy,
Gary Zenitsky,
Huajun Jin,
Vellareddy Anantharam,
Arthi Kanthasamy,
Chuan He,
Anumantha G. Kanthasamy
Affiliations
Emir Malovic
Parkinson’s Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
Alyssa Ealy
Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA
Cameron Miller
Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA
Ahyoung Jang
Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA
Phillip J. Hsu
Department of Chemistry, University of Chicago, Chicago, IL, USA
Souvarish Sarkar
Parkinson’s Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
Dharmin Rokad
Parkinson’s Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
Cody Goeser
Parkinson’s Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
Aleah Kristen Hartman
Parkinson’s Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
Allen Zhu
Department of Chemistry, University of Chicago, Chicago, IL, USA
Bharathi Palanisamy
Parkinson’s Disorder Research Laboratory, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
Gary Zenitsky
Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA
Huajun Jin
Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA
Vellareddy Anantharam
Isakson Center for Neurological Disease Research, University of Georgia, Athens, GA, USA; Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA
Arthi Kanthasamy
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
Chuan He
Department of Chemistry, University of Chicago, Chicago, IL, USA
Anumantha G. Kanthasamy
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; Corresponding author
Summary: 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.
