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NEDD4-binding protein 1 suppresses HBV replication by regulating HBV RNAs

ABSTRACT: Background and Aims Chronic infection with hepatitis B virus (HBV) has been known to cause liver cirrhosis and hepatocellular carcinoma. Although nucleos(t)ide analogs are mainly used for the treatment of HBV, they require long-term administration and may lead to the emergence of drug resistance. Therefore, to identify targets for the development of novel anti-HBV therapies, we screened HBV-suppressive host factors using RNA-bnding protein (RBP) expression plasmids library. Approach and Results We screened the RBP library by generating overexpressing RBP cell lines and observing anti-HBV effect. As a result, we identified NEDD4-binding protein 1 (N4BP1) as a candidate showing anti-HBV effect. In hepatocellular carcinoma cell lines, overexpression of N4BP1 decreased the relaxed circular DNA (rcDNA) levels, while suppression of N4BP1 expression increased rcDNA levels. Restoring N4BP1 expression in N4BP1 knockout cells regained the anti-HBV effect of N4BP1. Next, we constructed KH-like and RNase domain-deficient mutants of N4BP1 and examined their effects on HBV replication, and found that both the KH-like and RNase domains are required for its anti-HBV effect. N4BP1 suppresses the step where pregenomic RNA (pgRNA) is synthesized in the HBV life cycle by promoting degradation of pgRNA. Transcriptome analyses of primary human hepatocytes overexpressing N4BP1 suggested that N4BP1 may have anti-HBV activity independent of other host factors. Conclusions In summary, N4BP1 was found to be a novel anti-HBV factor. N4BP1 inhibited HBV replication by promoting pgRNA degradation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225322 | GEO | 2025/01/08

REPOSITORIES: GEO

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Project description:Hepatitis B virus (HBV) causes both acute and chronic liver inflammation. Approximately 600,000 CHB patients each year die of HBV-related diseases such as cirrhosis and liver cancer. Therefore, CHB remains a global health concern. Although there have been anti-HBV agents for treating CHB, they have some limitations including viral-drug resistance and adverse effects. Type III IFN or IFN-λ is promising to use as anti-HBV agents because of its anti-viral activities like type I IFNs. In addition, the expression of its receptor, IFNLR1, is limited only in epithelial cells including hepatocytes. Thus, treatment with IFN-lambda results in less side effects compared to IFN-alpha treatment. IFN-lambdas have been shown to inhibit the replication of several viruses including IAV, DENV, EMCV, HIV, HCV, and HBV; however, there have been no studies on the effects of IFN-λ3, the highest activity among other subtypes, on HBV replication. Therefore, this study aims to determine antiviral activities of IFN-λ3 against HBV replication and to investigate its molecular mechanism responsible for suppressing HBV propagation. The results showed that HBV transcripts and amount of intracellular HBV DNA were decreased in HepG2.2.15 cells, stable HBV-transfected hepatoblastoma cell line, treated with IFN-λ3 in a dose-dependent manner. This indicated that IFN-λ3 could inhibit HBV replication. Next, we performed quantitative proteomics to investigate the proteome changes in HepG2.2.15 treated with IFN-λ3. The proteins that changed their expressions were involved in several biological processes such as defense to viral infection, immune responses, cell-cell adhesion, transcription, translation, and metabolism. We further confirmed the proteomics results by immunoblotting assay. Consistent with MS data, it found that the expression of OAS3, SAMHD1 and STAT1 were increased as a result of IFN-λ3 stimulation. These results indicated that proteomics results were reproducible and reliable. Finally, we proposed 3 possible mechanisms involved in suppressing HBV replication including i.) IFN-λ3 induced anti-viral proteins affecting many steps in HBV life cycle ii.) IFN-λ3 promoted antigen processing and antigen presentation and iii.) IFN-λ3 rescued RIG-I signaling to promote both type I and type III IFN production.

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NEDD4-binding protein 1 suppresses HBV replication by regulating HBV RNAs

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