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Aerobic glycolysis supports hepatitis B virus biosynthesis through interaction between viral surface antigen and pyruvate kinase isoform M2

By Yi-Hsuan Wu, Yi Yang, Ching-Hung Chen, Chia-Jen Hsiao, Tian-Neng Li, Kuan-Ju Liao, Bor-Sen Chen, Lily Hui-Ching Wang

Posted 10 Aug 2020
bioRxiv DOI: 10.1101/2020.08.10.244038

As an intracellular pathogen, the reproduction of hepatitis B virus (HBV) depends on the occupancy of host metabolism machinery. Here we test a hypothesis if HBV may govern intracellular biosynthesis to achieve a productive reproduction. To test this hypothesis, we set up an affinity purification screen for host factors that interact with viral large surface antigen (LHBS). This identified pyruvate kinase isoform M2 (PKM2), a key regulator of glucose metabolism, as a binding partner of LHBS. We showed that the expression of LHBS affected oligomerization of PKM2 in hepatocytes, and thereby increased glucose consumption and lactate production, a phenomenon known as aerobic glycolysis. Interestingly, recovering PKM2 activity in hepatocytes by chemical activators, TEPP-46 or DASA-58, reduced biosynthesis of viral surface and core antigens. In addition, reduction of glycolysis by culturing in low-glucose condition or treatment with 2-deoxyglucose also decreased biosynthesis of viral surface antigen, without affecting general host proteins. Finally, TEPP-46 largely suppressed proliferation of LHBS-positive cells on 3-dimensional agarose plates, but showed no effect on the traditional 2-dimensional cell culture. Taken together, these results indicate that virus-induced metabolic switch may support de novo biosynthesis of HBV in hepatocytes. In addition, aerobic glycolysis is likely essential for LHBS-mediated oncogenesis. Accordingly, restriction of glucose metabolism may be considered as a novel strategy to restrain viral mediated biosynthesis and oncogenesis during chronic HBV infection.

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