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Complementarity between epsilon and phi sequences in pregenomic RNA influences hepatitis B virus replication efficiency.

ABSTRACT: Hepatitis B virus (HBV) replication requires the viral polymerase to reverse transcribe the 3.5-kb pregenomic viral RNA within the nucleocapsid. It has been proposed that a sequence element designated phi (phi), which is located 32 nucleotides upstream of the 3' DR1 pregenomic RNA sequence and is complementary to epsilon, is required for efficient minus-strand synthesis because it may mediate the translocation of the viral polymerase plus the three nucleotide primer from epsilon to DR1. A mutation in phi has been identified which can be compensated for with a complementary mutation in epsilon. This observation supports the suggestion that epsilon and phi base pair during the process of polymerase translocation from epsilon to DR1. However, additional mutations in phi were not complemented by the corresponding mutations in epsilon indicating that the functional recognition of epsilon and epsilon/phi stem-loop structures by polymerase probably requires both sequence- and structure-specific information.

SUBMITTER: Oropeza CE

PROVIDER: S-EPMC1850982 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Complementarity between epsilon and phi sequences in pregenomic RNA influences hepatitis B virus replication efficiency.

Oropeza Claudia E CE McLachlan Alan A

Virology 20061023 2

Hepatitis B virus (HBV) replication requires the viral polymerase to reverse transcribe the 3.5-kb pregenomic viral RNA within the nucleocapsid. It has been proposed that a sequence element designated phi (phi), which is located 32 nucleotides upstream of the 3' DR1 pregenomic RNA sequence and is complementary to epsilon, is required for efficient minus-strand synthesis because it may mediate the translocation of the viral polymerase plus the three nucleotide primer from epsilon to DR1. A mutati ...[more]

PMID: 17056086

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Project description:Encapsidation of pregenomic RNA (pgRNA) is a crucial step in hepatitis B virus (HBV) replication. Binding by viral polymerase (Pol) to the epsilon stem-loop (ε) on the 5'-terminal region (TR) of pgRNA is required for pgRNA packaging. However, the detailed mechanism is not well understood. RNA-binding motif protein 24 (RBM24) inhibits core translation by binding to the 5'-TR of pgRNA. Here, we demonstrate that RBM24 is also involved in pgRNA packaging. RBM24 directly binds to the lower bulge of ε via RNA recognition submotifs (RNPs). RBM24 also interacts with Pol in an RNA-independent manner. The alanine-rich domain (ARD) of RBM24 and the reverse transcriptase (RT) domain of Pol are essential for binding between RBM24 and Pol. In addition, overexpression of RBM24 increases Pol-ε interaction, whereas RBM24 knockdown decreases the interaction. RBM24 was able to rescue binding between ε and mutant Pol lacking ε-binding activity, further showing that RBM24 mediates the interaction between Pol and ε by forming a Pol-RBM24-ε complex. Finally, RBM24 significantly promotes the packaging efficiency of pgRNA. In conclusion, RBM24 mediates Pol-ε interaction and formation of a Pol-RBM24-ε complex, which inhibits translation of pgRNA and results in pgRNA packing into capsids/virions for reverse transcription and DNA synthesis.IMPORTANCE Hepatitis B virus (HBV) is a ubiquitous human pathogen, and HBV infection is a major global health burden. Chronic HBV infection is associated with the development of liver diseases, including fulminant hepatitis, hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. A currently approved vaccine can prevent HBV infection, and medications are able to reduce viral loads and prevent liver disease progression. However, current treatments rarely achieve a cure for chronic infection. Thus, it is important to gain insight into the mechanisms of HBV replication. In this study, we found that the host factor RBM24 is involved in pregenomic RNA (pgRNA) packaging and regulates HBV replication. These findings highlight a potential target for antiviral therapeutics of HBV infection.

Dataset Information

Complementarity between epsilon and phi sequences in pregenomic RNA influences hepatitis B virus replication efficiency.

Publications

Complementarity between epsilon and phi sequences in pregenomic RNA influences hepatitis B virus replication efficiency.

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