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

Abstract

As an intracellular pathogen, the reproduction of the 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 large viral surface antigens (LHBS). This identified pyruvate kinase isoform M2 (PKM2), a key regulator of glucose metabolism, as a binding partner of viral surface antigens. We showed that the expression of viral LHBS affected oligomerization of PKM2 in hepatocytes, thereby increasing glucose consumption and lactate production, a phenomenon known as aerobic glycolysis. Reduction of PKM2 activity was also validated in several different models, including HBV-infected HepG2-NTCP-C4 cells, adenovirus mediated HBV gene transduction and transfection with a plasmid containing complete HBV genome on HuH-7 cells. We found the recovery of PKM2 activity in hepatocytes by chemical activators, TEPP-46 or DASA-58, reduced expressions of viral surface and core antigens. In addition, reduction of glycolysis by culturing in low-glucose condition or treatment with 2-deoxyglucose also decreased expressions 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 HBV-induced metabolic switch may support its own translation 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 protein synthesis and subsequent oncogenesis during chronic HBV infection.

Mitochondria-mediated oxidative stress during viral infection

“…Other evidence for redox regulation of viral protein activity is illustrated by the observation that glutathionylation of cysteine residues Cys 67 and Cys 95 modulates HIV-1 protease activity [30]. Redox regulation of HIV-1 protease activity is believed to allow timely virus maturation and prevents premature host cell death, given the ability of this viral protein to cleave host prosurvival Bcl-2 protein [31].…”

“…Control of ROS production through metabolic switch Metabolic reprogramming has long been known as a viral strategy to generate all the molecules and metabolites necessary for optimal virus production [64]. More specifically, several viruses, such as HBV, HCV, HIV-1, and SARS-CoV2, have been reported to induce a metabolic switch to aerobic glycolysis in a manner reminiscent of the Warburg effect observed in cancer [65][66][67][68]. The metabolic switch to aerobic glycolysis has been described as an important underlying mechanism to ensure the generation of anabolic intermediates required for proliferation of cancer cells, and likely serves a similar function during viral infection for the synthesis of viral progeny.…”

Ca2+/Calmodulin-Dependent Protein Kinase II Inhibits Hepatitis B Virus Replication from cccDNA via AMPK Activation and AKT/mTOR Suppression

“…HBV has been shown to induce metabolic reprogramming to provide energy for HBV replication [ 6 , 7 , 8 ]. HBV infection increases glucose uptake, glycolytic metabolism, and lipid accumulation, which drive hepatic tissue damage resulting in the development of cirrhosis and HCC [ 9 , 10 , 11 ].…”

“…HBV infection increases glucose uptake, glycolytic metabolism, and lipid accumulation, which drive hepatic tissue damage resulting in the development of cirrhosis and HCC [ 9 , 10 , 11 ]. Although many metabolic proteins are involved in HBV replication [ 6 , 7 , 8 , 9 , 10 , 11 ], the underlying signaling pathway associated with metabolism during HBV replication has not yet been clearly determined. Evaluation of the metabolic signaling pathways associated with HBV replication showed that the AMPK activator metformin, which is used to treat patients with type 2 diabetes, suppressed the syntheses of HBe and HBs antigens and HBV replicative intermediate (RI) DNAs [ 12 ].…”

The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis

“…This effect initially occurs in tumor cells and is called the “Warburg” effect. Many studies have reported that aerobic glycolysis occurs in microglia ( Cheng et al, 2021a ; Wang et al, 2021a ), NK cells, and monocytes under different pathological conditions ( Cheng et al, 2016 ; Sheppard et al, 2021 ) and even virus-infected macrophages ( Wu et al, 2021 ). It is found that the serum and neutrophils of SARS-CoV-2 patients contain high lactate content, which is caused by elevated glycolysis ( McElvaney et al, 2020 ; Jia et al, 2021 ).…”