ENTR1 stabilizes MAVS by inhibiting NIX-mediated mitophagy to restrict BPIV3 and VSV replication

Endosome-associated trafficking regulator 1 (ENTR1) is implicated in cell Apoptosis, cytokinesis, and adipogenesis, but its role in Antiviral innate immunity has not been elucidated. In this study, we identify ENTR1 as a positive regulatory factor for type I interferon (IFN-I) signaling pathway, which suppresses bovine parainfluenza virus type 3 (BPIV3) and vesicular stomatitis virus (VSV) replication. Further investigations revealed that ENTR1 deficiency enhanced Nip3-like protein X (NIX)-mediated Mitophagy, leading to accelerated degradation of mitochondrial Antiviral signaling protein (MAVS) during viral Infection. Mechanistically, ENTR1 knockout resulted in increased accumulation of NIX on mitochondria, which promoted the autophagic degradation of MAVS. Importantly, silencing NIX rescued MAVS protein levels and significantly reduced viral titers in ENTR1-deficient cells. Moreover, NIX silencing prevented the degradation of MAVS and consequently reduced viral titers in ENTR1-deficient cells. Consequently, our findings reveal a novel regulatory axis in which ENTR1 stabilizes MAVS by suppressing NIX-dependent Mitophagy, thereby enhancing Antiviral IFN-I responses. This study not only uncovers a previously unrecognized function of ENTR1 in Antiviral immunity but also identifies ENTR1 as a potential target for developing broad-spectrum Antiviral therapeutics against RNA viruses.

Bovine parainfluenza virus type 3 (BPIV3); Endosome-associated trafficking regulator 1 (ENTR1); Mitochondrial antiviral signaling protein (MAVS); Mitophagy; Vesicular stomatitis virus (VSV).