Alphavirus Nsp3 protein hijacks receptor-mediated mitophagy via BNIP3L/NIX to dampen IFN response and promote viral replication

Alphaviruses encompass a variety of human and animal pathogens, such as getah virus (GETV), chikungunya virus (CHIKV), and Sindbis virus (SINV). Increasing evidence suggests that innate immunity plays an important role in host resistance to alphavirus infection, while alphaviruses have evolved multiple strategies to evade host antiviral innate immunity. Mitochondria, as key immune hubs, play a central role in the initiation of innate antiviral responses. It remains unclear whether alphaviruses inhibit innate immune responses by manipulating mitochondria. In this study, we found that GETV infection damages mitochondrial structure and function, as shown by mitochondrial membrane potential depolarization, reduction in mitochondrial numbers, and an imbalance in mitochondrial dynamics. GETV infection induces mitophagy in host cells and promotes viral replication. Nsp3 protein of alphaviruses (CHIKV, SINV, GETV) can directly trigger receptor-mediated mitophagy through its interaction with BNIP3L/NIX. Knockdown of BNIP3L could alleviate mitophagy caused by GETV infection. Mitophagy induced by alphavirus Nsp3 protein leads to degradation of MAVS which inhibits the IFN response and promotes viral replication. Collectively, our results demonstrated that alphaviruses Nsp3 serves as a novel virulence factor, inducing BNIP3L-mediated mitophagy to degrade MAVS and evade the host immune response.