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

Abstract

<i>N</i>⁶-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-β 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-β 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-β stimulation, thereby mediating m⁶A modification of a subset of ISGs to restrict their expression. The phase transition of WTAP promotes the interaction with nucleus-translocated transcription factor STAT1, recruits MTC to the promoter regions of ISGs and directs 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. Our findings unveil a novel mechanism by which WTAP phase transition controls immune homeostasis via transcription factor-MTC-driven dynamic m⁶A modification, thereby proposing a potential therapeutic target for alleviating immune dysregulation.