Heteromeric LGP2-MDA5 receptor complexes drive antiviral signaling

The innate immune receptor MDA5 serves as a first line of defense against RNA viruses by recognizing viral double-stranded RNA (dsRNA) and initiating antiviral signaling. MDA5 is upregulated by another RLR family member known as LGP2, which has been proposed to enhance MDA5 activity by recruiting MDA5 to dsRNA. However, it has remained unclear whether LGP2 functions solely as a transient recruitment factor or actively participates in signaling-competent MDA5 filaments. Here, we demonstrate that LGP2 does more than recruiting MDA5 to dsRNA, and that LGP2 becomes an integral component of MDA5 filaments. Mechanistically, LGP2 stabilizes MDA5 filaments and reduces the number of MDA5 molecules required to nucleate stable signaling-competent filaments. This interplay between the two RLR proteins is mediated by specific dsRNA-dependent interactions between the C-terminal tail of LGP2 and MDA5, resulting in a network of contacts that is essential for LGP2-mediated enhancement of MDA5 signaling. Together, these findings provide new mechanistic insight into how LGP2 regulates the assembly and persistence of signaling-competent MDA5 filaments, establishing filament architecture and stability as key determinants of MDA5 signaling. Collectively, this work provides a mechanistic framework for understanding LGP2-mediated regulation of MDA5 signaling and advances our knowledge of the molecular mechanisms governing antiviral immunity.