Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double-stranded RNA.

Foster, Graham R.; Ackrill, Andrew M.; Goldin, Robert; Kerr, Ian M.; Thomas, Howard; Stark, George Stark

doi:10.1073/pnas.88.7.2888

Cited by 144 publications

(63 citation statements)

References 38 publications

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“…Several different mechanisms have been proposed to account for this effect (Sen & Ransohoff, 1993). HBV capsid protein (referred to as the HBc protein) has been shown to trans-suppress IFN-β gene expression (Whitten et al, 1991) ; whilst in another study, the expression of HBV polymerase terminal protein was shown to inhibit IFN-induced 6-16 gene expression (Foster et al, 1991). This latter result, however, is still debated (Foster et al, 1995).…”

Section: Introductionmentioning

confidence: 82%

Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein.

Rosmorduc

Sirma

Soussan

et al. 1999

Journal of General Virology

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Section: Introductionmentioning

confidence: 82%

Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein.

Rosmorduc

Sirma

Soussan

et al. 1999

Journal of General Virology

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“…Our results support this idea and define a molecular basis for the synergy between IFNs and sodium butyrate in hepatoma growth inhibition. Furthermore, a recent study has reported that hepatitis B viral terminal protein shuts off IFN-induced gene expression by interfering with the formation of ISGF-3 and inhibited cellular responses to IFN-α and IFN-γ (Foster et al, 1991). The authors suggested that, in patients with chronic hepatitis B virus infection, an imbalance in HBV RNA and polymerase production may generate sufficient free polymerases or terminal proteins to give rise to IFN-resistant cells.…”

Section: Discussionmentioning

confidence: 99%

Sodium butyrate enhances STAT 1 expression in PLC/PRF/5 hepatoma cells and augments their responsiveness to interferon-α

Wc¹,

Chuang²

1999

Br J Cancer

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Interferons (IFNs) are cytokines that are involved in the regulation of diverse cellular functions, including modulation of immune responses, inhibition of proliferation, and induction of resistance to viral and bacterial infection (Gutterman, 1994). IFNs employ a unique signalling pathway for rapid induction of gene expression by utilizing two groups of critical elements to transduce the signals from cell surface receptor to nuclear events. The first is the janus family kinases (JAKs), a group of tyrosine kinases containing JAK1, JAK2, JAK3 and TYK2, and the second is STAT (signal transducers and activators of transcription) proteins, a group of latent cytoplasmic transcription factors which are activated by phosphorylation (Darnell, 1997;Pellegrini and Dusanter-Fourt, 1997). Upon IFN stimulation, receptor-associated JAKs are phosphorylated and activated and these kinases, in turn, phosphorylate and activate STAT proteins which then translocate from cytoplasm to nucleus and direct transcriptional activation of various effector genes. The essential role of JAKs and STATs in IFN signalling pathway has been demonstrated by the IFN-resistant phenotypes of cells lacking the JAK or STAT gene products (Muller et al, 1993;Xu et al, 1994).Recent studies have shown that IFNs are the most promising anti-viral agents for the treatment of patients with chronic hepatitis B. These cytokines have been reported to suppress hepatitis B virus (HBV) enhancer activity, reduce virus replication and activate hepatocellular gene expression in cultured liver cells (Tur-Kaspa et al, 1990;Zhang and McLachlan, 1994). Additionally, results from clinical trials also demonstrated that IFNs caused inhibition of HBV replication and reduction of hepatitis B surface antigen (HBsAg) expression (Alexander et al, 1987;Korenman et al, 1991). These studies suggest that IFNs are useful anti-viral drugs for the treatment of patients with viral hepatitis. However, the use of IFNs in the therapy of liver cancer seems discouraging. Although several studies have shown that IFNs exerted growth-inhibitory effects on human hepatoma cells (Lai et al, 1989;Boue et al, 1990), other works showed that patients with advanced hepatocellular carcinoma were resistant to IFNs (Nair et al, 1985;Sachs et al, 1985). However, the molecular basis of this resistance is not clear.Recent studies have indicated that the responses of cells to IFNs could be modulated by regulating the expression or the activity of JAKs and STATs. It has been found that elevated activity of JAKs enhanced the anti-tumour effects of IFNs to lymphoblastoid cells (Lee et al, 1997). Similarly, induction of STATs gene expression by retinoic acids in IFN-unresponsive breast cancer cells and myeloid leukaemia cells permitted growth inhibition by IFNs (Kolla et al, 1996;Weihua et al, 1997). These data suggest that the resistance of cancer cells to IFNs may be due to a relative deficiency of IFN signalling molecules and argue that overexpression of these signalling molecules may restore the responsiveness o...

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“…The RT protein is known to interact with a number of cellular proteins, including molecular chaperone proteins (13,15), the helicase DDX3 (52), and the translation factor eIF4E (22). The RT protein is also thought to be cytotoxic when overexpressed and has been reported to affect cellular functions such as interferon signaling and gene expression (2,8,14,53). Perhaps, the formation of nucleotide abducts of cellular proteins, i.e., RT-mediated protein priming from these cellular proteins, can contribute to the cellular effects of the RT protein and thus could play a role in cytotoxicity and viral pathogenesis, especially if substantial amounts of the RT protein are unpackaged (58).…”

Section: Discussionmentioning

confidence: 99%

Cryptic Protein Priming Sites in Two Different Domains of Duck Hepatitis B Virus Reverse Transcriptase for Initiating DNA Synthesis In Vitro

Boregowda

Zhu

et al. 2011

J Virol

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Initiation of reverse transcription in hepadnaviruses is accomplished by a unique protein-priming mechanism whereby a specific Y residue in the terminal protein (TP) domain of the viral reverse transcriptase (RT) acts as a primer to initiate DNA synthesis, which is carried out by the RT domain of the same protein. When separate TP and RT domains from the duck hepatitis B virus (DHBV) RT protein were tested in a transcomplementation assay in vitro, the RT domain could also serve, unexpectedly, as a protein primer for DNA synthesis, as could a TP mutant lacking the authentic primer Y (Y96) residue. Priming at these other, so-called cryptic, priming sites in both the RT and TP domains shared the same requirements as those at Y96. A mini RT protein with both the TP and RT domains linked in cis, as well as the full-length RT protein, could also initiate DNA synthesis using cryptic priming sites. The cryptic priming site(s) in TP was found to be S/T, while those in the RT domain were Y and S/T. As with the authentic TP Y96 priming site, the cryptic priming sites in the TP and RT domains could support DNA polymerization subsequent to the initial covalent linkage of the first nucleotide to the priming amino acid residue. These results provide new insights into the complex mechanisms of protein priming in hepadnaviruses, including the selection of the primer residue and the interactions between the TP and RT domains that is essential for protein priming.The Hepadnaviridae family includes the hepatitis B virus (HBV), a global human pathogen that chronically infects hundreds of millions and causes a million fatalities yearly, and related animal viruses such as the duck hepatitis B virus (DHBV) (40). Hepadnaviruses contain a small (ϳ3-kb), partially double-stranded DNA genome that is replicated through an RNA intermediate, called pregenomic RNA (pgRNA) by reverse transcription (39, 43). The virally encoded reverse transcriptase (RT) is unique among known RTs in its structure and function (14). RT is composed of four domains. The Nterminal TP (terminal protein) is conserved among all hepadnaviruses but absent from all other known RTs and is required for viral reverse transcription. The spacer domain, which does not have any known role in RT functions, connects TP to the central RT domain and the C-terminal RNase H domain. Both the RT and the RNase H domains share sequence homology with other RTs, including the RT active-site motif YMDD and the catalytic RNase H residues (4, 5, 35, 57).A prerequisite for the initiation of reverse transcription in hepadnaviruses is the specific interaction between RT and a short RNA signal called ε located at the 5Ј end of pgRNA (33, 51). RT-ε interaction is required to activate the polymerase activity of RT and ε also serves as the template for the initial stage of viral reverse transcription (13,16,44,46,47,49).Instead of relying on an RNA primer to prime DNA synthesis, as is the case with most other RTs and DNA polymerases in general, the hepadnavirus RT uses a specific Y residue in the TP ...

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Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double-stranded RNA.

Cited by 144 publications

References 38 publications

Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein.

Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein.

Sodium butyrate enhances STAT 1 expression in PLC/PRF/5 hepatoma cells and augments their responsiveness to interferon-α

Cryptic Protein Priming Sites in Two Different Domains of Duck Hepatitis B Virus Reverse Transcriptase for Initiating DNA Synthesis In Vitro

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