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WTAP的相变调节干扰素刺激基因的m⁶A修饰。

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

作者信息

Cai Sihui, Zhou Jie, Luo Xiaotong, Zhang Chenqiu, Jin Shouheng, Ren Jian, Cui Jun

机构信息

MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.

Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China.

出版信息

Elife. 2025 May 27;13:RP100601. doi: 10.7554/eLife.100601.

Abstract

-methyladenosine (mA) is the most prevalent modification of mRNA which controls diverse physiological processes. Although mA 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 mA 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 mA MTC, undergoes dephosphorylation-regulated phase transition from aggregates to liquid-like condensates under IFN-β stimulation, thereby mediating mA 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 mA 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 mA 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 mA modification, thereby proposing a potential therapeutic target for alleviating immune dysregulation.

摘要

N6-甲基腺苷(mA)是mRNA中最普遍的修饰,它控制着多种生理过程。尽管有报道称mA修饰通过靶向IFN-β的mRNA和干扰素刺激基因(ISG)来调节I型干扰素(IFN)反应,但在IFN-β刺激期间,mA甲基转移酶复合物(MTC)如何快速响应以对新生mRNA进行修饰的详细机制仍不清楚。在这里,我们证明,mA MTC的衔接蛋白WTAP在IFN-β刺激下经历去磷酸化调节的相变,从聚集体转变为类液体凝聚物,从而介导一部分ISG的mA修饰以限制其表达。WTAP的相变促进了与核转位转录因子STAT1的相互作用,将MTC招募到ISG的启动子区域,并指导对ISG mRNA的共转录mA修饰。总的来说,我们的研究结果揭示了WTAP相变在通过转录因子和MTC的合作协调动态mA修饰来操纵信号通路和微调免疫反应方面的新调节作用。我们的研究结果揭示了一种新机制,即WTAP相变通过转录因子-MTC驱动的动态mA修饰来控制免疫稳态,从而为缓解免疫失调提出了一个潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10e2/12113268/a6a0d9894e1a/elife-100601-fig1.jpg

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