Requirements for cell rounding and surface protein down-regulation by Ebola virus glycoprotein

Francica, Joseph R.; Matukonis, Meghan K.; Bates, Paul

doi:10.1016/j.virol.2008.10.029

Cited by 44 publications

(58 citation statements)

References 47 publications

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“…We tested the effect of GP tagged with the endoplasmic reticulum (ER) retention motif, KKMP. This mutant is efficiently retained in the ER, with minimal surface expression as determined by immunofluorescence microscopy and flow cytometry (18). GP-KKMP failed to restore tetherin-restricted VLP budding, despite ample expression of the GP in cell lysates (Fig.…”

Section: Resultsmentioning

confidence: 90%

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.

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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: 90%

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.

Self Cite

314

386

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“…Some studies have indicated that GP 1,2 induces active internalization of surface molecules required for attachment and communication with the immune system and also promotes cell death (51,52). Other studies have suggested that GP 1,2 sterically occludes surface factors without actually reducing cell viability (20,53). In one study, it was reported that overexpression of GP 1,2 , through mutation of the GP editing site, resulted in enhanced cytopathicity, with the recombinant virus growing to lower infectivity titers (19).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have indicated that EBOV GP 1,2 is metabolically costly to synthesize and process and that high levels of GP 1,2 expression are toxic to host cells (18,19). While the exact mechanism of toxicity has been debated, it has been observed that overexpression of GP 1,2 leads to cell rounding and detachment as well as loss of detection of some cell surface markers (20)(21)(22). Importantly, EBOV regulates GP 1,2 expression via an RNA-editing mechanism whereby full-length GP 1,2 mRNA is produced by slippage of the viral polymerase at an editing site (23,24).…”

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confidence: 99%

Less Is More: Ebola Virus Surface Glycoprotein Expression Levels Regulate Virus Production and Infectivity

Mohan

et al. 2015

J Virol

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The Ebola virus (EBOV) surface glycoprotein (GP 1,2 ) mediates host cell attachment and fusion and is the primary target for host neutralizing antibodies. Expression of GP 1,2 at high levels disrupts normal cell physiology, and EBOV uses an RNA-editing mechanism to regulate expression of the GP gene. In this study, we demonstrate that high levels of GP 1,2 expression impair production and release of EBOV virus-like particles (VLPs) as well as infectivity of GP 1,2 -pseudotyped viruses. We further show that this effect is mediated through two mechanisms. First, high levels of GP 1,2 expression reduce synthesis of other proteins needed for virus assembly. Second, viruses containing high levels of GP 1,2 are intrinsically less infectious, possibly due to impaired receptor binding or endosomal processing. Importantly, proteolysis can rescue the infectivity of high-GP 1,2 -containing viruses. Taken together, our findings indicate that GP 1,2 expression levels have a profound effect on factors that contribute to virus fitness and that RNA editing may be an important mechanism employed by EBOV to regulate GP 1,2 expression in order to optimize virus production and infectivity. IMPORTANCEThe Ebola virus (EBOV), as well as other members of the Filoviridae family, causes severe hemorrhagic fever that is highly lethal, with up to 90% mortality. The EBOV surface glycoprotein (GP 1,2 ) plays important roles in virus infection and pathogenesis, and its expression is tightly regulated by an RNA-editing mechanism during virus replication. Our study demonstrates that the level of GP 1,2 expression profoundly affects virus particle production and release and uncovers a new mechanism by which Ebola virus infectivity is regulated by the level of GP 1,2 expression. These findings extend our understanding of EBOV infection and replication in adaptation of host environments, which will aid the development of countermeasures against EBOV infection.

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“…Such effects could even be something that GP does as a contribution to the Ebola virus assembly process. In support of such a scenario, GP has recently been reported to impede the recognition of several cell surface proteins, including ␤1 integrin (CD29) and major histocompatibility complex (MHC) class I (84,87,95), through a mechanism of glycan-mediated steric hindrance (20,76). However, the mucin-like domain of GP that is necessary for this effect (20) is not required for GP to counteract tetherin (44).…”

Section: Discussionmentioning

confidence: 99%

Anti-Tetherin Activities of HIV-1 Vpu and Ebola Virus Glycoprotein Do Not Involve Removal of Tetherin from Lipid Rafts

Lopez

Yang

Exline

et al. 2012

J Virol

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BST-2/tetherin is an interferon-inducible host restriction factor that blocks the release of newly formed enveloped viruses. It is enriched in lipid raft membrane microdomains, which are also the sites of assembly of several enveloped viruses. Viral anti-tetherin factors, such as the HIV-1 Vpu protein, typically act by removing tetherin from the cell surface. In contrast, the Ebola virus glycoprotein (GP) is unusual in that it blocks tetherin restriction without apparently altering its cell surface localization. We explored the possibility that GP acts to exclude tetherin from the specific sites of virus assembly without overtly removing it from the cell surface and that lipid raft exclusion is the mechanism involved. However, we found that neither GP nor Vpu had any effect on tetherin's distribution within lipid raft domains. Furthermore, GP did not prevent the colocalization of tetherin and budding viral particles. Contrary to previous reports, we also found no evidence that GP is itself a raft protein. Together, our data indicate that the exclusion of tetherin from lipid rafts is not the mechanism used by either HIV-1 Vpu or Ebola virus GP to counteract tetherin restriction.

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Requirements for cell rounding and surface protein down-regulation by Ebola virus glycoprotein

Cited by 44 publications

References 47 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

Less Is More: Ebola Virus Surface Glycoprotein Expression Levels Regulate Virus Production and Infectivity

Anti-Tetherin Activities of HIV-1 Vpu and Ebola Virus Glycoprotein Do Not Involve Removal of Tetherin from Lipid Rafts

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