YTHDF1-CLOCK axis contributes to pathogenesis of allergic airway inflammation through LLPS [mRNA-seq]

N6-methyladenosine (m6A) modification has been implicated in many cell processes and diseases. YTHDF1, a translation-facilitating m6A reader, is not previously shown to be related to allergic airway inflammation. Here, we report that YTHDF1 is highly expressed in allergic airway epithelial cells (AECs) and asthmatic patients, and influences proinflammatory responses. CLOCK, a subunit of the circadian clock pathway, is the direct target of YTHDF1. YTHDF1 augments CLOCK translation in an m6A-dependent manner. Allergens enhance the liquid‒liquid phase separation (LLPS) of YTHDF1 and drive the formation of a complex comprising dimeric YTHDF1 and CLOCK mRNA, which is distributed to stress granules (SGs). Moreover, YTHDF1 strongly activates NLRP3 inflammasome production and IL-1β secretion, leading to airway inflammatory responses, but these phenotypes are abolished by deleting CLOCK. These findings demonstrate that YTHDF1 is an important regulator of asthmatic airway inflammation, suggesting a potential therapeutic target for allergic airway inflammation. we assessed the impact of YTHDF1 on allergic airway inflammation; explored the mechanism by which YTHDF1 regulated the target gene CLOCK, and further inferred the clinical significance of its action in human subjects.

N6-甲基腺嘌呤（m6A）修饰参与诸多细胞进程与疾病发生。YTHDF1作为一类促进翻译的m6A阅读蛋白，此前尚未被证实与变应性气道炎症相关。本研究证实，YTHDF1在变应性气道上皮细胞（AECs）及哮喘患者体内呈高表达，并可调控促炎反应。生物钟通路亚基CLOCK是YTHDF1的直接靶标基因，YTHDF1以m6A依赖的方式增强CLOCK的翻译效率。变应原可促进YTHDF1发生液-液相分离（LLPS），并驱动由二聚体YTHDF1与CLOCK mRNA组成的复合物形成，该复合物可靶向转运至应激颗粒（SGs）中。此外，YTHDF1可显著激活NLRP3炎症小体的生成与白细胞介素1β（IL-1β）的分泌，进而介导气道炎症反应，但该效应可因CLOCK的敲除而被完全消除。本研究结果表明，YTHDF1是哮喘性气道炎症的关键调控因子，提示其可作为变应性气道炎症的潜在治疗靶点。本研究评估了YTHDF1对变应性气道炎症的影响，阐明了YTHDF1调控靶基因CLOCK的分子机制，并进一步推导了其在人体中的临床作用价值。