Molecular mechanism of MDA5 nucleation and filament formation by LGP2

LGP2, a RIG-I-like receptor, plays a crucial role in antiviral immunity by enhancing MDA5 activity against specific viral infections. Here, using biochemical assays, cryo-electron microscopy (cryo-EM), and high-speed atomic force microscopy, we reveal that LGP2 initially binds to the ends of double-stranded RNA (dsRNA) and subsequently translocates along the RNA via ATP hydrolysis. Our cryo-EM structure demonstrates that LGP2 forms filament-like assemblies with MDA5 along the internal region of dsRNA, promoting MDA5 filament nucleation. Additionally, LGP2 and MDA5 form short RNA filaments, which are further cross-bridged via caspase activation and recruitment domain (CARD)-CARD interactions, leading to the formation of filament microclusters. These microclusters, in turn, stimulate mitochondrial antiviral signaling (MAVS) filament formation. Our findings uncover a dynamic interplay between LGP2 and MDA5, revealing a previously unrecognized mechanism that enhances antiviral immune responses.