Role of Endosomal Cathepsins in Entry Mediated by the Ebola Virus Glycoprotein

Schornberg, Kathryn L.; Matsuyama, Shutoku; Kabsch, Kirsten; Delos, Sue E.; Bouton, Amy H.; White, Judith M.

doi:10.1128/jvi.80.8.4174-4178.2006

Cited by 393 publications

(642 citation statements)

References 22 publications

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“…Medina et al (53) have observed that a Zaire ebolavirus GP 1,2 lacking residues 241-496 nonetheless retained its ability to mediate entry of a pseudotyped retrovirus. (18,21).…”

Section: Discussionmentioning

confidence: 99%

“…However, its deletion enhances rather than decreases the efficiency of GP 1,2 -mediated infection (13, 16 -18). Receptor binding is followed by endocytosis of the virions (19), acidification of the endocytotic vesicle (4,5,20), and proteolytic processing of GP 1 by endosomal cathepsins (18,21). Conformational changes in the filoviral GP 2 subunit facilitate lipid mixing and fusion of the viral and cellular membranes, in a sequence of steps thought similar to those mediated by orthomyxoviral and retroviral transmembrane proteins (22)(23)(24)(25).…”

mentioning

confidence: 99%

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Conserved Receptor-binding Domains of Lake Victoria Marburgvirus and Zaire Ebolavirus Bind a Common Receptor

Kuhn

Radoshitzky

Guth

et al. 2006

Journal of Biological Chemistry

120

136

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The GP 1,2 envelope glycoproteins (GP) of filoviruses (marburg-and ebolaviruses) mediate cell-surface attachment, membrane fusion, and entry into permissive cells. Here we show that a 151-amino acid fragment of the Lake Victoria marburgvirus GP 1 subunit bound filoviruspermissive cell lines more efficiently than full-length GP 1 . An homologous 148-amino acid fragment of the Zaire ebolavirus GP 1 subunit similarly bound the same cell lines more efficiently than a series of longer GP 1 truncation variants. Neither the marburgvirus GP 1 fragment nor that of ebolavirus bound a nonpermissive lymphocyte cell line. Both fragments specifically inhibited replication of infectious Zaire ebolavirus, as well as entry of retroviruses pseudotyped with either Lake Victoria marburgvirus or Zaire ebolavirus GP 1,2 . These studies identify the receptor-binding domains of both viruses, indicate that these viruses utilize a common receptor, and suggest that a single small molecule or vaccine can be developed to inhibit infection of all filoviruses.

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“…Medina et al (53) have observed that a Zaire ebolavirus GP 1,2 lacking residues 241-496 nonetheless retained its ability to mediate entry of a pseudotyped retrovirus. (18,21).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Conserved Receptor-binding Domains of Lake Victoria Marburgvirus and Zaire Ebolavirus Bind a Common Receptor

Kuhn

Radoshitzky

Guth

et al. 2006

Journal of Biological Chemistry

120

136

View full text Add to dashboard Cite

show abstract

“…2). By affecting either viral entry 31,32 or exit 33,34 , these and other proteases could influence viral cellular tropisms and perhaps interactions between glycoprotein domains and antibodies (FIGS 2,3). Moreover, Barrientos and Rollin reported recently that endosomal proteolytic enzymes, including cathepsins, were released from EBOV-infected cells, that this release was more pronounced in cells infected with a more lytic variant of EBOV and that cytopathicity was diminished by the cathepsin inhibitor E64 (REF.…”

Section: Box 1 | Filovirus-disease Basicsmentioning

confidence: 99%

How Ebola and Marburg viruses battle the immune system

2007

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PantropicTending towards the capacity to infect a wide range of cells and organs. CoagulopathyRefers to a group of conditions of the blood-clotting system in which bleeding is prolonged and excessive. Cell tropismA virus's affinity for or tendency towards preferential infection of certain cells. How Ebola and Marburg viruses battle the immune systemMansour Mohamadzadeh* ‡ , Lieping Chen ‡ , and Alan L. Schmaljohn* Abstract | The filoviruses Ebola and Marburg have emerged in the past decade from relative obscurity to serve now as archetypes for some of the more intriguing and daunting challenges posed by such agents. Public imagination is captured by deadly outbreaks of these viruses and reinforced by the specter of bioterrorism. As research on these agents has accelerated, it has been found increasingly that filoviruses use a combination of familiar and apparently new ways to baffle and battle the immune system. Filoviruses have provided thereby a new lens through which to examine the immune system itself. R E V I E W S Report Documentation PageForm Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number.

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“…The fit curves are plotted using the corresponding open circles, X's, and open diamonds, respectively. (17,19), and EnvA is well incorporated into VSV pseudotyped particles (Z. Chen, unpublished data), We therefore assessed the fusion activity of EnvA on VSV pseudovirions. As seen with ASLV-A ( Fig.…”

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confidence: 99%

Cysteines Flanking the Internal Fusion Peptide Are Required for the Avian Sarcoma/Leukosis Virus Glycoprotein To Mediate the Lipid Mixing Stage of Fusion with High Efficiency

Delos¹,

Brecher

Chen³

et al. 2008

J Virol

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We previously showed that the cysteines flanking the internal fusion peptide of the avian sarcoma/leukosis virus subtype A (ASLV-A) Env (EnvA) are important for infectivity and cell-cell fusion. Here we define the stage of fusion at which the cysteines are required. The flanking cysteines are dispensable for receptor-triggered membrane association but are required for the lipid mixing step of fusion, which, interestingly, displays a high pH onset and a biphasic profile. Second-site mutations that partially restore infection partially restore lipid mixing. These findings indicate that the cysteines flanking the internal fusion peptide of EnvA (and perhaps by analogy Ebola virus glycoprotein) are important for the foldback stage of the conformational changes that lead to membrane merger.The avian sarcoma/leukosis virus (ASLV) Env protein is unusual among class I fusion proteins in that it contains an internal fusion peptide, a characteristic it shares with filovirus (Ebola virus and Marburg virus) glycoproteins. These fusion peptides are flanked by two Cys residues, which, based on structural and mutagenesis evidence, likely form a disulfide bond (9, 21). The ASLV fusion peptide contains one proline, and the filovirus fusion peptides contain two prolines, at their centers. Previous work has shown that these Pro residues are important for fusion (4,8). The fusion peptide of EnvA is operationally defined as residues 22 to 37 of the transmembrane (TM) subunit. We previously provided evidence that the Pro in the middle of this peptide (P29) requires a ␤-turn structure (4) at some stage of fusion. We subsequently showed that the two Cys residues (C9 and C45) that define the likely disulfide-bonded loop encompassing the fusion peptide are required for infectivity and cell-cell fusion (5). In this study, we identified the specific stage of fusion that requires the Cys residues that flank the EnvA fusion peptide.To begin our studies, we asked if the defect was in the first step of fusion: target membrane binding. Accordingly, we determined the ability of murine leukemia virus pseudotyped virions (10) bearing either wild-type EnvA or an EnvA harboring double Cys-to-Ser mutations at both positions 9 and 45 of the TM subunit (referred to below as EnvAC9,45S) to bind to target membranes in a receptor-dependent manner (6, 7, 15). As seen in Fig. 1, wild-type murine leukemia virus pseudovirions bound liposomes and floated to the top of the gradient when either the quail (lane 1) or the chicken (lane 5) form of the soluble Tva receptor (sTva) was used (7). In the absence of sTva, all of the pseudovirions remained at the bottom of the gradient (Fig. 1, lane 12). Similar receptor-dependent membrane association was observed for EnvAC9,45S (Fig. 1). These data show that the Cys residues (C9 and C45) that define the loop encompassing the fusion peptide are not required for receptor-triggered binding of EnvA-bearing virus particles to target membranes.We then asked whether the cysteines are required for EnvA to reach the lipid mixing ...

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Role of Endosomal Cathepsins in Entry Mediated by the Ebola Virus Glycoprotein

Cited by 393 publications

References 22 publications

Conserved Receptor-binding Domains of Lake Victoria Marburgvirus and Zaire Ebolavirus Bind a Common Receptor

Conserved Receptor-binding Domains of Lake Victoria Marburgvirus and Zaire Ebolavirus Bind a Common Receptor

How Ebola and Marburg viruses battle the immune system

Cysteines Flanking the Internal Fusion Peptide Are Required for the Avian Sarcoma/Leukosis Virus Glycoprotein To Mediate the Lipid Mixing Stage of Fusion with High Efficiency

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