Autophagy is involved in various stages of the viral life cycle and modulates viral replication. Coronaviruses have developed several strategies to exploit autophagy for their benefit. Nevertheless, the exact mechanisms through which the infectious bronchitis virus (IBV) influences autophagy remain inadequately understood. Here, we demonstrate that IBV infection of chicken embryonic kidney (CEK) cells activates the AKT-mTOR signaling pathway to suppress autophagosome formation and mitophagy. Further investigation reveals that the viral spike protein (S) inhibits cellular autophagy by interacting with the mitophagy receptor FUNDC1. However, FUNDC1-mediated mitophagy promotes degradation of the viral nucleocapsid (N) protein and restricts IBV replication. To counteract this host defense mechanism, the S protein competitively binds to the LC3-interacting region (LIR) motif of FUNDC1, thereby disrupting its interaction with LC3 and ultimately suppressing mitophagy. Molecular docking analysis revealed that a conserved asparagine residue at position 240 (N240) in the S1 subunit of the IBV S protein is essential for binding to FUNDC1. Furthermore, reverse genetics demonstrated that an IBV mutant with an N240A substitution exhibited reduced pathogenicity in the kidneys, trachea, and lungs of specific-pathogen-free (SPF) chickens compared to the wild-type virus. Collectively, these findings unveil a novel mechanism by which IBV antagonizes host mitophagy and provide new insights into the host-virus interplay within the context of autophagic regulation.IMPORTANCEIBV has evolved a mechanism to counteract the host's antiviral defense. Specifically, the viral spike (S) protein blocks a form of autophagy called mitophagy by binding to the mitochondrial receptor FUNDC1. Normally, FUNDC1 helps cells eliminate damaged mitochondria and restricts IBV replication by promoting the degradation of the viral nucleocapsid protein. By interfering with this process, the S protein enhances viral survival. We further identified a single conserved amino acid in the S protein that is critical for this function, and mutation of this residue weakened IBV in chickens. These findings reveal how IBV manipulates host defenses and suggest new strategies for controlling coronavirus infections.
Zhao et al. (Mon,) studied this question.