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Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs

Filoviruses Ebola (EBOV) and Marburg (MARV) are devastating high-priority pathogens capable of causing explosive outbreaks with high human mortality rates. The matrix proteins of EBOV and MARV, as well as eVP40 and mVP40, respectively, are the key viral proteins that drive virus assembly and egress...

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Autores principales: Shepley-McTaggart, Ariel, Schwoerer, Michael Patrick, Sagum, Cari A., Bedford, Mark T., Jaladanki, Chaitanya K., Fan, Hao, Cassel, Joel, Harty, Ronald N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918931/
https://www.ncbi.nlm.nih.gov/pubmed/33673144
http://dx.doi.org/10.3390/v13020288
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author Shepley-McTaggart, Ariel
Schwoerer, Michael Patrick
Sagum, Cari A.
Bedford, Mark T.
Jaladanki, Chaitanya K.
Fan, Hao
Cassel, Joel
Harty, Ronald N.
author_facet Shepley-McTaggart, Ariel
Schwoerer, Michael Patrick
Sagum, Cari A.
Bedford, Mark T.
Jaladanki, Chaitanya K.
Fan, Hao
Cassel, Joel
Harty, Ronald N.
author_sort Shepley-McTaggart, Ariel
collection PubMed
description Filoviruses Ebola (EBOV) and Marburg (MARV) are devastating high-priority pathogens capable of causing explosive outbreaks with high human mortality rates. The matrix proteins of EBOV and MARV, as well as eVP40 and mVP40, respectively, are the key viral proteins that drive virus assembly and egress and can bud independently from cells in the form of virus-like particles (VLPs). The matrix proteins utilize proline-rich Late (L) domain motifs (e.g., PPxY) to hijack specific host proteins that contain WW domains, such as the HECT family E3 ligases, to facilitate the last step of virus–cell separation. We identified E3 ubiquitin ligase Smad Ubiquitin Regulatory Factor 2 (SMURF2) as a novel interactor with VP40 that positively regulates VP40 VLP release. Our results show that eVP40 and mVP40 interact with the three WW domains of SMURF2 via their PPxY motifs. We provide evidence that the eVP40–SMURF2 interaction is functional as the expression of SMURF2 positively regulates VLP egress, while siRNA knockdown of endogenous SMURF2 decreases VLP budding compared to controls. In sum, our identification of novel interactor SMURF2 adds to the growing list of identified host proteins that can regulate PPxY-mediated egress of VP40 VLPs. A more comprehensive understanding of the modular interplay between filovirus VP40 and host proteins may lead to the development of new therapies to combat these deadly infections.
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spelling pubmed-79189312021-03-02 Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs Shepley-McTaggart, Ariel Schwoerer, Michael Patrick Sagum, Cari A. Bedford, Mark T. Jaladanki, Chaitanya K. Fan, Hao Cassel, Joel Harty, Ronald N. Viruses Article Filoviruses Ebola (EBOV) and Marburg (MARV) are devastating high-priority pathogens capable of causing explosive outbreaks with high human mortality rates. The matrix proteins of EBOV and MARV, as well as eVP40 and mVP40, respectively, are the key viral proteins that drive virus assembly and egress and can bud independently from cells in the form of virus-like particles (VLPs). The matrix proteins utilize proline-rich Late (L) domain motifs (e.g., PPxY) to hijack specific host proteins that contain WW domains, such as the HECT family E3 ligases, to facilitate the last step of virus–cell separation. We identified E3 ubiquitin ligase Smad Ubiquitin Regulatory Factor 2 (SMURF2) as a novel interactor with VP40 that positively regulates VP40 VLP release. Our results show that eVP40 and mVP40 interact with the three WW domains of SMURF2 via their PPxY motifs. We provide evidence that the eVP40–SMURF2 interaction is functional as the expression of SMURF2 positively regulates VLP egress, while siRNA knockdown of endogenous SMURF2 decreases VLP budding compared to controls. In sum, our identification of novel interactor SMURF2 adds to the growing list of identified host proteins that can regulate PPxY-mediated egress of VP40 VLPs. A more comprehensive understanding of the modular interplay between filovirus VP40 and host proteins may lead to the development of new therapies to combat these deadly infections. MDPI 2021-02-12 /pmc/articles/PMC7918931/ /pubmed/33673144 http://dx.doi.org/10.3390/v13020288 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shepley-McTaggart, Ariel
Schwoerer, Michael Patrick
Sagum, Cari A.
Bedford, Mark T.
Jaladanki, Chaitanya K.
Fan, Hao
Cassel, Joel
Harty, Ronald N.
Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs
title Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs
title_full Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs
title_fullStr Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs
title_full_unstemmed Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs
title_short Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs
title_sort ubiquitin ligase smurf2 interacts with filovirus vp40 and promotes egress of vp40 vlps
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918931/
https://www.ncbi.nlm.nih.gov/pubmed/33673144
http://dx.doi.org/10.3390/v13020288
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