The innate immune system is the first line of defense against microbial pathogens and relies on pattern-recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs). MDA5, a RIG-I-like receptor, recognizes long double-stranded RNA (dsRNA) and activates downstream signaling pathways through filament assembly. However, the role of MDA5's ATPase activity in regulating filament formation and immune homeostasis has remained unclear.
In a study published in Cell Research, a research team led by Prof. LIU Jiaquan from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, in collaboration with Prof. Jin Zhong from the Shanghai Institute of Immunity and Infection, reveals the molecular mechanism by which MDA5 utilizes ATP-driven one-dimensional motion to suppress spontaneous filament formation and maintain immune homeostasis.
Using single-molecule imaging and biochemical assays, the researchers discovered that MDA5 functions as an ATP-hydrolysis-driven molecular motor capable of translocating along dsRNA in a one-dimensional manner. Multiple MDA5 motors can cooperatively load onto the same dsRNA, but their movements are asynchronous, preventing spontaneous filament formation and aberrant activation. Furthermore, LGP2, a key regulator of MDA5 signaling, was found to arrest MDA5 motion, thereby promoting microfilament assembly. This unique assembly mechanism highlights the critical role of one-dimensional motion in higher-order protein oligomerization.
The study also demonstrated that ATPase-deficient MDA5 mutants (e.g., R337G and M854K, which are associated with autoimmune diseases) lack the ability to perform one-dimensional motion, leading to spontaneous filament formation on RNA and aberrant activation on self-RNA. These findings provide a molecular basis for understanding autoimmune diseases linked to MDA5 dysfunction.
This work not only uncovers the molecular mechanism by which MDA5 maintains immune homeostasis through one-dimensional motion but also offers potential therapeutic targets for autoimmune diseases.
The study was jointly conducted by Prof. Jiaquan Liu from the Center for Excellence in Molecular Cell Science, CAS, and Prof. Jin Zhong from the Shanghai Institute of Immunity and Infection. Xiaopeng Han (Ph.D. student from the Center for Excellence in Molecular Cell Science), Ming Rao (Postdoctoral researcher), and Yu Chang (Ph.D. student from the Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences) are co-first authors of this study.
This research was supported by Dr. Ling-Ling Chen, Dr. Fajian Hou, Dr. Shao-Qing Zhang from the Center for Excellence in Molecular Cell Science the Chinese Academy of Sciences, the Strategic Priority Research Program of CAS, the National Key R&D Program of China, the Key Laboratory of RNA Function and Application, and the National Natural Science Foundation of China.
Reference: https://doi.org/10.1038/s41422-025-01183-8
Appendix：
