Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite the primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in 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. Here, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in hepatocellular carcinoma (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 (mTORC2), which can prevent YAP degradation. mTORC2-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, provide an alternative paradigm for the cellular effects of a tumor promoting virus.

中文翻译：

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HBV 重塑肝细胞癌中的 PP2A 复合物以重新连接激酶信号传导


乙型肝炎病毒 （HBV） 感染通过诱导炎症和细胞应激来促进肝癌的发生。尽管 HBV 主要对肿瘤发生产生间接影响，但 HBV 与 HCC 中的复发性基因组表型相关，表明它影响已确诊 HCC 的生物学特性。表征 HBV 与宿主蛋白的相互作用以及 HBV 对 HCC 起始和维持的机制贡献可以提供对 HCC 生物学的见解并揭示治疗脆弱性。在这里，我们使用亲和纯化质谱法全面绘制了肝细胞癌 （HCC） 中 HBV 与人类蛋白质之间的 145 种物理相互作用网络。HBV 蛋白靶向的宿主因子子集在非 HBV 相关 HCC 中优先突变，表明它们与 HBV 的相互作用影响 HCC 生物学。HBV 与参与 mRNA 剪接、有丝分裂信号传导和 DNA 修复的蛋白质相互作用，后者与 HBV 癌蛋白 X （HBx） 相互作用。HBx 通过从 PP2A 全酶中排除纹状体调节亚基来重塑 PP2A 磷酸酶复合物，HBx 对 PP2A 的影响导致 Hippo 激酶激活。同时，HBx 激活了 mTOR 复合物 2 （mTORC2），可以防止 YAP 降解。在人 HCC 标本和小鼠 HCC 模型中观察到 mTORC2 介导的 YAP 上调，并且可以靶向 mTOR 激酶抑制剂。因此，HBV 与宿主蛋白的相互作用重新连接 HCC 信号传导，而不是直接激活促有丝分裂途径，为促肿瘤病毒的细胞效应提供了一种替代范例。