HBV Remodels PP2A Complexes to Rewire Kinase Signaling in Hepatocellular Carcinoma

Abstract Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite a primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in hepatocellular carcinoma (HCC), suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. In this study, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in HCC. A subset of the host factors targeted by HBV proteins were preferentially mutated in non–HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2, which can prevent YAP degradation. mTOR complex 2–mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, providing an alternative paradigm for the cellular effects of a tumor-promoting virus. Significance: Integrative proteomic and genomic analysis of HBV/host interactions illuminated modifiers of hepatocellular carcinoma behavior and key signaling mechanisms in advanced disease, which suggested that HBV may have therapeutically actionable effects.