Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation

Abstract

Hepatitis B virus (HBV), a highly persistent pathogen causing hepatocellular carcinoma (HCC), takes full advantage of host machinery, presenting therapeutic targets. Here we aimed to identify novel druggable host cellular factors using the reporter HBV we have recently generated. In an RNAi screen of G protein-coupled receptors (GPCRs), GPCR39 (GPR39) appeared as the top hit to facilitate HBV proliferation. Lentiviral overexpression of active GPR39 proteins and an agonist enhanced HBV replication and transcriptional activities of viral promoters, inducing the expression of CCAAT/enhancer binding protein (CEBP)-β (CEBPB). Meanwhile, GPR39 was uncovered to activate the heat shock response, upregulating the expression of proviral heat shock proteins (HSPs). In addition, glioma-associated oncogene homologue signaling, a recently reported target of GPR39, was suggested to inhibit HBV replication and eventually suppress expression of CEBPB and HSPs. Thus, GPR39 provirally governed intracellular circuits simultaneously affecting the carcinopathogenetic gene functions. GPR39 and the regulated signaling networks would serve as antiviral targets, and strategies with selective inhibitors of GPR39 functions can develop host-targeted antiviral therapies preventing HCC.

MDM2 Influences ACE2 Stability and SARS-CoV-2 Uptake

“…These candidates were further tested for their effect against the Rift Valley Fever Virus (RVFV) and Herpes Simplex Virus (HSV-1). Depletion of GPR39, a regulator of heat shock proteins and the hedgehog pathway [ 35 ], showed highly virus-specific effects: While GRP39 depletion increased SARS-CoV-2 replication, it decreased the propagation of all other viruses tested ( Figure 1 B–F). Better growth of SARS-CoV-2 and VSV was seen upon knockout of SLC30A1 ( Figure 1 B,C), which has been reported to elevate intracellular zinc levels and hence inhibit caspase activation and apoptosis [ 36 , 37 ].…”

The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target

“…Later, it has been shown to activate all GPR39 inducible pathways [ 35 ]. Since its discovery, TC-G 1008 has proven to be a potent agonist and a very valuable tool in characterizing the physiological functions and therapeutic potential of GPR39 activation, published by a number of studies to date [ 30 , 31 , 32 , 35 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. However, most studies have not verified their findings in GPR39 −/− settings, which would be critical in order to confirm that the observed effects are indeed GPR39-dependent.…”

“…Interestingly, one study indicated GPR39 activation in hepatitis B virus proliferation. GPR39, activated by TC-G 1008, was shown to induce the transcription of viral promoters and proviral heat shock proteins, suggesting that GPR39 inhibition could be studied as a novel strategy to combat viral replication in cells [ 66 ].…”