WTAP Regulates Inflammation by Fine-tuning the STAT3 Signaling Axis via m6A Modification and Phase Separation
N6-methyladenosine (m6A), a rapidly developing field in recent years, is involved in various inflammatory states and has attracted a lot of attention, but the underlying mechanism is still lacking. Here, we show that WTAP is markedly upregulated in a p65-dependent manner under multiple inflammatory stimuli. Mechanically, upregulated WTAP undergoes phase separation to facilitate the aggregation of "writer" complex and the deposition of m6A to IL6ST mRNA, promoting the protein output of IL6ST and the activation of IL6/STAT3 axis. Furthermore, WTAP promotes the protein abundance of IL15Ra and IL18Ra, which may modulate the lymphocyte activation via STAT3 signaling. Myeloid deficiency of WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. High WTAP expression is associated with increased m6A marks in many inflammatory diseases. Thus, the proinflammatory effect of WTAP by targeting STAT3 signaling axis is a risk-increasing mechanism, suggesting potential therapeutic strategies to alleviate various hyperinflammation in clinic.