RACK1 inhibits fowl adenovirus serotype 4 replication by targeting the viral protein Hexon for ubiquitin-proteasome degradation.

Fowl adenovirus serotype 4 (FAdV-4), the most pathogenic member of the genus Aviadenovirus, within the family Adenoviridae, primarily induces hepatitis-hydropericardium syndrome (HHS), leading to high morbidity and mortality in chickens. The capsid protein Hexon has been established as a core virulence factor of FAdV-4, but the underlying interaction mechanisms between Hexon and the host remain to be fully elucidated. In this study, we identified that the host protein RACK1 endogenously interacts with the Hexon, and that overexpression of RACK1 significantly inhibited FAdV-4 replication, whereas knockdown of RACK1 markedly promoted this process. Mechanistically, the interaction between RACK1 and Hexon promotes the degradation of Hexon via the ubiquitin-proteasome pathway, thus suppressing FAdV-4 replication. Our results further enrich the understanding of the interaction between Hexon and the host and identifies a novel host factor interaction that may inform future strategies for controlling HHS.