Journal Article

Elevated WTAP promotes hyperinflammation by increasing m6A modification in inflammatory disease models

Ling, Tao, Luo, Guanzheng, Chen, Hongxuan, Xia, Guomeng, Yuan, Shaochun, Ge, Yong, Xie, Xiongmei, Chen, Rong, Huang, Jingrong, Xu, Anlong, Cheng, Youxiang, Lin, Yi, Liu, Biaodi

2024

Overview

Emerging evidence has linked the dysregulation of N 6 -methyladenosine (m 6 A) modification to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high levels of m 6 A modification in a variety of hyperinflammatory states are p65-dependent because Wilms tumor 1–associated protein (WTAP), a key component of the “writer” complex, is transcriptionally regulated by p65, and its overexpression can lead to increased levels of m 6 A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of the writer complex to nuclear speckles and the deposition of m 6 A marks on transcriptionally active inflammatory transcripts, thereby accelerating the proinflammatory response. Further, a myeloid deficiency in WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of the m 6 A writer complex to reduce the global m 6 A levels by targeting the phase separation of WTAP may be a potential and promising therapeutic strategy for alleviating hyperinflammation.

• Publisher: American Society for Clinical Investigation
• Subject: Adenosine - analogs & derivatives / Adenosine - metabolism / Animals / Cell Cycle Proteins / Cytokines / Disease Models, Animal / Genes / Homeostasis / Humans / Immunology / Inflammation / Inflammation - genetics / Inflammation - metabolism / Inflammation - pathology / Inflammatory diseases / Ligands / Lipopolysaccharides / Mice / Mice, Knockout / N6-methyladenosine / Phosphorylation / Proteins / RNA Splicing Factors - genetics / RNA Splicing Factors - metabolism / Salmonella / Sepsis / Sepsis - genetics / Sepsis - metabolism / Sepsis - pathology / Transcription Factor RelA - genetics / Transcription Factor RelA - metabolism / Writers / WT1 protein