Identification and characterization of host factor VCPIP1 as a multi-functional positive regulator of hepatitis B virus

Hepatitis B virus (HBV) encodes the regulatory protein HBx that plays crucial roles in viral life cycle and cellular processes through interacting with viral and cellular proteins. Identifying HBx-interacting proteins may reveal novel aspects of host-virus interactions. In this work, proximity labeling coupled with proteomic analysis identified multiple HBx-interacting host factors, and among these, valosin-containing protein-interacting protein 1 (VCPIP1) was confirmed to directly bind HBx and reduce its proteasomal degradation, corroborating a recent report. In addition to upregulating HBx-expressing HBV, we showed that VCPIP1 also positively regulates mutant HBV lacking HBx expression. This novel HBx-independent function of VCPIP1 was shown to involve its association with one viral promoter/enhancer element, which upregulated the latter's promoter and enhancer activities. These results establish VCPIP1 as a positive regulator of HBV that acts through multiple, diverse mechanisms and might also contribute toward revealing novel cellular functions of VCPIP1.