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

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. [Display omitted] •Mn exposure induces proinflammatory response in astrocytes by reducing YTHDF2•YTHDF2 targets MAP2K4 mRNA for decay in astrocytes•Mn-induced YTHDF2 downregulation upregulates the proinflammatory SEK1 pathway•Selective depletion of YTHDF2 in astrocytes induces astrogliosis in mice Molecular mechanism of gene regulation; Molecular network; Neurotoxicology; Cell biology; Transcriptomics