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bioRxiv · 10.1101/2024.07.18.604157

Phase transition of WTAP regulates m6A modification of interferon-stimulated genes

Cai, S.·Zhou, J.·Luo, X.·Zhang, C.·Jin, S.·Ren, J.·Cui, J.
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Abstract

N6-methyladenosine (m6A) is the most prevalent modification of mRNA which controls diverse physiological processes. Although m6A modification has been reported to regulate type I interferon (IFN) responses by targeting the mRNA of IFN-{beta} and the interferon stimulated genes (ISGs), the detailed mechanism of how m6A methyltransferase complex (MTC) rapidly responds to conduct the modification on nascent mRNA during IFN-{beta} stimulation remains largely unclear. Here, we demonstrate that WTAP, the adaptor protein of m6A MTC, undergoes dephosphorylation-regulated phase transition from aggregates to liquid-like condensates under IFN-{beta} stimulation, thereby mediates m6A modification of a subset of ISG mRNAs to restrict their expression. The phase transition of WTAP promotes the interaction with nucleus-translocated transcription factor STAT1, which recruits MTC to the promoter regions of ISGs and directing the co-transcriptional m6A modification on ISG mRNAs. Collectively, our findings reveal a novel regulatory role of WTAP phase transition in manipulating signaling pathways and fine-tuning immune response by orchestrating dynamic m6A modification through the cooperation of transcription factors and MTC.

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Cai, S., Zhou, J., Luo, X., Zhang, C., Jin, S., Ren, J., Cui, J.. 2024-07-22. Phase transition of WTAP regulates m6A modification of interferon-stimulated genes. https://doi.org/10.1101/2024.07.18.604157

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