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doi:10.1038/sj/gt/3301154

Gene Ther

2000

DOI: 10.1038/sj/gt/3301154

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Abstract: Efficient transfer of proteins or nucleic acids across cellular membranes is a major problem in cell biology. Recently the existence of a fusogenic sequence was predicted in the junction area of the PreS2-and S-domain of the hepatitis-B virus surface antigens. We have identified cell permeability as a novel property of the PreS2-domain. Cell permeability of PreS2 is not restricted to hepatocytes. PreS2 translocates in an energy-independent manner into cells and is evenly distributed over the cytosol. Detailed … Show more

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Cited by 4 publications

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Integrity of c-Raf-1/MEK signal transduction cascade is essential for hepatitis B virus gene expression

et al. 2003

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The genome of hepatitis B virus (HBV) encodes two transcriptional activators: the HBx protein and the PreS2-activator large surface protein (LHBs). Both proteins trigger activation of c-Raf-1/MEK kinase cascade. In case of HBx this can be mediated by a PKC-independent and Ras-dependent mechanism, in case of LHBs activation is PKC-dependent and does not require Ras. Selective destruction of either LHBs-or of HBx-specific activation does not result in significant decrease of viral production from transfected HepG2 cells. Simultaneous inhibition of LHBs-and HBx-dependent activation by blocking signaling steps common to both activators, using trans dominant negative c-Raf-1-or MEK-specific inhibitors, abolished HBV gene expression. In accordance with this no HBV propagation was observed after transfection of a mutated HBV genome defective for HBx-and PreS2-activator function. A detailed analysis revealed that the observed inhibition of HBV-propagation is because of a significant reduction of HBV-specific RNA resulting in an inhibition of the de novo synthesis of viral compounds (viral proteins and nucleic acid) and not by blocking secretion or assembly of the virus. Based on these results we conclude that transcriptional-activator function, mediated by the cRaf-1/MEK signaling cascade, is essential for HBV gene expression.

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Integrity of c-Raf-1/MEK signal transduction cascade is essential for hepatitis B virus gene expression

et al. 2003

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Identification of a structural motif crucial for infectivity of hepatitis B viruses

Stoeckl

Funk²,

Kopitzki³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Infectious entry of hepatitis B viruses (HBV) has nonconventional facets. Here we analyzed whether a cell-permeable peptide [translocation motif (TLM)] identified within the surface protein of human HBV is a general feature of all hepadnaviruses and plays a role in the viral life cycle. Surface proteins of all hepadnaviruses contain conserved functional TLMs. Genetic inactivation of the duck HBV TLMs does not interfere with viral morphogenesis; however, these mutants are noninfectious. TLM mutant viruses bind to cells and are taken up into the endosomal compartment, but they cannot escape from endosomes. Processing of surface protein by endosomal proteases induces their exposure on the virus surface. This unmasking of TLMs mediates translocation of viral particles across the endosomal membrane into the cytosol, a prerequisite for productive infection. The ability of unmasked TLMs to translocate processed HBV particles across cellular membranes was shown by confocal immunofluorescence microscopy and by infection of nonpermissive cell lines with HBV processed in vitro with endosomal lysate. Based on these data, we propose an infectious entry mechanism unique for hepadnaviruses that involves virus internalization by receptor-mediated endocytosis followed by processing of surface protein in endosomes. This processing activates the function of TLMs that are essential for viral particle translocation through the endosomal membrane into the cytosol and productive infection.cell permeability ͉ envelope protein ͉ virus entry I nfection with human hepatitis B virus (HBV) can cause acute or chronic inflammation of the liver (1, 2). HBV is the prototype member of the hepadnaviridae family, which encompasses members infecting woodchucks, ground squirrels, and avian viruses isolated from, e.g., pekin ducks, gray herons, and storks.Duck HBV (DHBV) is a well characterized model system of hepadnaviral infection (3). Cultures of primary duck hepatocytes (PDHs) can be readily established and efficiently infected (3, 4) and therefore provide a suitable tool for analyzing the early steps of hepadnaviral infection on the molecular level. As for HBV (5-7), it is known that DHBV infection is initiated by attachment of the virus particle to the hepatocyte surface via the pre-S domain of the viral surface protein L (8, 9). In DHBV there are two surface proteins embedded in the lipid envelope: The major S protein, a transmembrane protein that encompasses 167 aa, and the L protein, consisting of the S domain N-terminally extended by the 160-aa pre-S domain. Previous work suggested that DHBV enters the cell by receptor-mediated endocytosis (10-13). The mechanism that allows internalized viral particles to escape from the endocytic pathway remained elusive.Recently, a cell-permeable peptide [translocation motif (TLM)] was identified in the pre-S domain of HBV (14). The TLM is a 12-aa-encompassing domain that forms an amphipathic ␣-helix. It mediates an energy-and receptor-independent transfer of peptides, nucleic acids, and proteins when fus...

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An Unconventional NLS is Critical for the Nuclear Import of the Influenza A Virus Nucleoprotein and Ribonucleoprotein

Cros

García‐Sastre

Palese

2005

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135

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Replication of the RNAs of influenza virus occurs in the nucleus of infected cells. The nucleoprotein (NP) has been shown to be important for the import of the viral RNA into the nucleus and has been proposed to contain at least three different nuclear localization signals (NLSs). Here, an import assay in digitonin-permeabilized cells was used to further define the contribution of these NLSs. Mutation of the unconventional NLS impaired the nuclear import of the NP. A peptide bearing the unconventional NLS could inhibit the nuclear import of the NP in this import assay and prevent the NP-karyopherin a interaction in a binding assay confirming the crucial role of this signal. Interestingly, a peptide containing the SV40 T antigen NLS was unable to inhibit the nuclear import of NP or the NP-karyopherin a interaction, suggesting that the NP and the SV40 T antigen do not share a common binding site on karyopherin a. We also investigated the question of which NLS(s) is/are necessary for the viral ribonucleoprotein complex to enter the nucleus. We found that the peptide containing the unconventional NLS efficiently inhibited the nuclear import of the ribonucleoprotein complexes. This finding suggests that the unconventional NLS is the major signal necessary not only for the nuclear transport of free NP but also for the import of the ribonucleoprotein complexes. Finally, viral replication could be specifically inhibited by a membranepermeable peptide containing the unconventional NLS, confirming the crucial role of this signal during the replicative cycle of the virus.Key words: influenza virus, nuclear import, nuclear localization signal, nucleoprotein The genome of influenza A viruses is composed of eight single-stranded negative sense RNA segments (1). These RNA molecules are tightly associated with several viral proteins, including the nucleoprotein (NP) and the polymerase subunits (PB1, PB2 and PA) forming viral ribonucleoprotein (vRNP) complexes. Following attachment to the cell surface, the virus is internalized by receptor-mediated endocytosis. Acidification of the vesicle triggers the fusion activity of the viral hemagglutinin. Viral and endosomal membranes fuse, releasing the vRNPs into the cytoplasm. Concomitantly, the viral core is acidified through the proton-channel activity of the viral M2 protein, resulting in an irreversible change in the M1 protein and its dissociation from the vRNP, a necessary step prior to entry of vRNP into the nucleus where viral transcription and replication take place (2,3).A challenge faced by the vRNPs is the translocation through the nuclear membrane. Incoming vRNPs as well as newly synthesized viral proteins must get into the nucleus. Nucleocytoplasmic trafficking is a tightly controlled process and only occurs through the nuclear pore complexes. These large structures (125 MDa) (4) are composed of nucleoporins and span both nuclear membranes with extensions in the nucleus and the cytoplasm (5,6). Molecules with a molecular weight of less than 40 000-50 000 are believed to d...

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Cited by 4 publications

References 14 publications

Integrity of c-Raf-1/MEK signal transduction cascade is essential for hepatitis B virus gene expression

Integrity of c-Raf-1/MEK signal transduction cascade is essential for hepatitis B virus gene expression

Identification of a structural motif crucial for infectivity of hepatitis B viruses

An Unconventional NLS is Critical for the Nuclear Import of the Influenza A Virus Nucleoprotein and Ribonucleoprotein

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