Ectodomain shedding of the glycoprotein GP of Ebola virus

Dolnik, Olga; Volchkova, Valentina A.; Garten, Wolfgang; Carbonnelle, Caroline; Becker, Stephan; Kahnt, Jörg; Ströher, Ute; Klenk, Hans‐Dieter; Volchkov, Viktor E.

doi:10.1038/sj.emboj.7600219

Cited by 154 publications

(163 citation statements)

References 43 publications

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“…Ebola infection produces several forms of the viral GP, including nonstructural GP (sGP), which shares the N-terminal 295 residues with full-length GP and is the primary product of the GP gene (11,12). Infection also yields soluble GP, which is shed from the cell surface by cleavage at the extracellular base of GP by the tumor necrosis factor ␣-converting enzyme (TACE) protease (13). We tested whether sGP and a ⌬TM form of GP (secGP), representing the TACE-cleaved protein, could restore Ebola VLP release in the presence of tetherin.…”

Section: Resultsmentioning

confidence: 99%

Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein

Kaletsky

Francica

Agrawal-Gamse

et al. 2009

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

314

376

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Mammalian cells employ numerous innate cellular mechanisms to inhibit viral replication and spread. Tetherin, also known as Bst-2 or CD317, is a recently identified, IFN-induced, cellular response factor that blocks release of HIV-1 and other retroviruses from infected cells. The means by which tetherin retains retroviruses on the cell surface, as well as the mechanism used by the HIV-1 accessory protein Vpu to antagonize tetherin function and promote HIV-1 release, are unknown. Here, we document that tetherin functions as a broadly acting antiviral factor by demonstrating that both human and murine tetherin potently inhibit the release of the filovirus, Ebola, from the surface of cells. Expression of the Ebola glycoprotein (GP) antagonized the antiviral effect of human and murine tetherin and facilitated budding of Ebola particles, as did the HIV-1 Vpu protein. Conversely, Ebola GP could substitute for Vpu to promote HIV-1 virion release from tetherin-expressing cells, demonstrating a common cellular target for these divergent viral proteins. Ebola GP efficiently coimmunoprecipitated with tetherin, suggesting that the viral glycoprotein directly interferes with this host antiviral factor. These results demonstrate that tetherin is a cellular antiviral factor that restricts budding of structurally diverse enveloped viruses. Additionally, Ebola has evolved a highly effective strategy to combat this antiviral response elicited in the host during infection.antiviral ͉ CD317 ͉ viral budding ͉ HIV-1 vpu ͉ Bst-2

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Section: Resultsmentioning

confidence: 99%

Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein

Kaletsky

Francica

Agrawal-Gamse

et al. 2009

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

314

376

View full text Add to dashboard Cite

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“…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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“…Recent data indicate that high levels of shed GP are present in the blood of EBOV-infected animals, suggesting that circulating GP might play an important role in disease pathogenesis by blocking the activity of EBOV-neutralising antibodies (Ref. 120). Although previous attempts were not completely successful in macaques, several new approaches warrant investigation before passive transfer of antibodies is abandoned as a potential therapy for EBOV HF.…”

Section: Research In Progress and Outstanding Research Questions Antimentioning

confidence: 99%

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

Geisbert

Hensley

2004

Expert Rev. Mol. Med.

111

106

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Ebola virus (EBOV) gained public notoriety in the last decade largely as a consequence of the highly publicised isolation of a new EBOV species in a suburb of Washington, DC, in 1989, together with the dramatic clinical presentation of EBOV infection and high case-fatality rate in Africa (near 90% in some outbreaks), and the unusual and striking morphology of the virus. Furthermore, there are no vaccines or effective therapies currently available. Progress in understanding the origins of the pathophysiological changes that make EBOV infections of humans so devastating has been slow, primarily because these viruses require special containment for safe research. However, an increasing understanding of the mechanisms of EBOV pathogenesis, facilitated by the development of new tools to elucidate critical regulatory elements in the viral life cycle, is providing new targets that can be exploited for therapeutic interventions. Notably, identifying factors triggering the haemorrhagic complications that characterise EBOV infections led to the development of a strategy to modulate coagulopathy; this therapeutic modality successfully mitigated the effects of EBOV haemorrhagic fever in nonhuman primates. This review summarises our current understanding of EBOV pathogenesis and discusses various approaches to therapeutic intervention based on our current understanding of how EBOV produces a lethal infection.

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Ectodomain shedding of the glycoprotein GP of Ebola virus

Cited by 154 publications

References 43 publications

Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein

Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein

How Ebola and Marburg viruses battle the immune system

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

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