CP204L Is a Multifunctional Protein of African Swine Fever Virus That Interacts with The VPS39 Subunit of HOPS Complex and Promotes Lysosome Clustering

Abstract

Virus replication depends on a complex interplay between viral and host proteins. In the case of African swine fever virus (ASFV), a large DNA virus, only few virus-host protein-protein interactions have been identified to date. In this study, we demonstrate that the ASFV protein CP204L directly interacts with the cellular homotypic fusion and protein sorting (HOPS) protein VPS39, blocking its association with the lysosomal HOPS complex, that modulates endolysosomal trafficking and promotes lysosome clustering. Instead, VPS39 is targeted to the sites of virus replication termed virus factories. Furthermore, we show that loss of VPS39 reduces the levels of virus proteins synthesized in the early phase of infection and delays ASFV replication but does not completely inhibit it. Collectively, these results identify a novel virus-host protein interaction that modulates host membrane rearrangement during infection and provide evidence that CP204L is a multifunctional protein engaged in distinct steps of the ASFV life cycle.