YTHDF1-CLOCK axis contributes to pathogenesis of allergic airway inflammation through LLPS
Jing Wang,
Yao Zhou,
Meng Zhang,
Yujiao Wu,
Qun Wu,
Wen Su,
Min Xu,
Jinhong Wu,
Min Zhang,
Jianwei Shuai,
Wei Tang,
Jiajia Lv,
Min Wu,
Zhenwei Xia
Affiliations
Jing Wang
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Surgery, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yao Zhou
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Meng Zhang
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yujiao Wu
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qun Wu
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wen Su
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Min Xu
Department of Surgery, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jinhong Wu
Department of Surgery, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Min Zhang
Department of Surgery, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jianwei Shuai
Joint Research Centre on Medicine, The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
Wei Tang
Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding Author
Jiajia Lv
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding Author
Min Wu
Joint Research Centre on Medicine, The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China; Corresponding author
Zhenwei Xia
Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author
Summary: N6-methyladenosine (m6A) modification has been implicated in many cell processes and diseases. YTHDF1, a translation-facilitating m6A reader, has not been previously shown to be related to allergic airway inflammation. Here, we report that YTHDF1 is highly expressed in allergic airway epithelial cells and asthmatic patients and that it 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. Moreover, YTHDF1 strongly activates NLRP3 inflammasome production and interleukin-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.
