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ATP-dependent one-dimensional movement maintains immune homeostasis by suppressing spontaneous MDA5 filament assembly

Xiao-Peng Han^1,† , Ming Rao^1,† , Yu Chang^2,3,4,† , Jun-Yan Zhu¹ , Jun Cheng¹ , Yu-Ting Li¹ , Wu Qiong¹ , Si-Chao Ye² , Qiurong Zhang¹ , Shao-Qing Zhang¹ , Ling-Ling Chen^1,5 , Fajian Hou^1,6 , Jin Zhong^2,3,4,* , Jiaquan Liu^1,*

¹State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
²Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
³School of Life Science and Technology, ShanghaiTech University, Shanghai, China
⁴Infectious Disease Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
⁵New Cornerstone Science Laboratory, Shenzhen, Guangdong, China
⁶Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
^†These authors contributed equally: Xiao-Peng Han, Ming Rao, Yu Chang
* Correspondence: Jin Zhong(jzhong@ips.ac.cn)Jiaquan Liu(liujiaquan@sibcb.ac.cn)

MDA5 is a RIG-I-like receptor (RLR) that recognizes viral double-stranded RNA (dsRNA) to initiate the innate immune response. Its activation requires filament formation along the dsRNA, which triggers the oligomerization of N-terminal caspase activation and recruitment domains. The ATPase activity of MDA5 is critical for immune homeostasis, likely by regulating filament assembly. However, the molecular basis underlying this process remains poorly understood. Here, we show that MDA5 operates as an ATP-hydrolysis-driven motor that translocates along dsRNA in a one-dimensional (1D) manner. Multiple MDA5 motors can cooperatively load onto a single dsRNA, but their movements rarely synchronize, inhibiting spontaneous filament formation and activation. LGP2, a key regulator of MDA5 signaling, recognizes MDA5 motors and blocks their movement, thereby promoting filament assembly through a translocation-directed mechanism. This unique assembly strategy underscores the role of 1D motion in higher-order protein oligomerization and reveals a novel mechanism for maintaining immune homeostasis.

https://doi.org/10.1038/s41422-025-01183-8

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