Ebola virus VP35 interacts non-covalently with ubiquitin chains to promote viral replication
Ebolavirus (EBOV) belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans. EBOV replication requires the activity of the viral polymerase complex, which includes the cofactor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination...
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| Veröffentlicht in: | PLoS biology 2024-02, Vol.22 (2), p.e3002544 |
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| creator | Rodríguez-Salazar, Carlos A van Tol, Sarah Mailhot, Olivier Gonzalez-Orozco, Maria Galdino, Gabriel T Warren, Abbey N Teruel, Natalia Behera, Padmanava Afreen, Kazi Sabrina Zhang, Lihong Juelich, Terry L Smith, Jennifer K Zylber, María Inés Freiberg, Alexander N Najmanovich, Rafael J Giraldo, Maria I Rajsbaum, Ricardo |
| description | Ebolavirus (EBOV) belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans. EBOV replication requires the activity of the viral polymerase complex, which includes the cofactor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface, and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity. Treatment with the compounds reduced replication of infectious EBOV in cells and in vivo in a mouse model. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity. |
| doi_str_mv | 10.1371/journal.pbio.3002544 |
| format | Article |
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EBOV replication requires the activity of the viral polymerase complex, which includes the cofactor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface, and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity. Treatment with the compounds reduced replication of infectious EBOV in cells and in vivo in a mouse model. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity.</description><identifier>ISSN: 1545-7885</identifier><identifier>ISSN: 1544-9173</identifier><identifier>EISSN: 1545-7885</identifier><identifier>DOI: 10.1371/journal.pbio.3002544</identifier><identifier>PMID: 38422166</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Addition polymerization ; Analysis ; Animals ; Chemical compounds ; Covalence ; Ebola virus ; Ebolavirus ; Ebolavirus - genetics ; Ectopic expression ; Genetic aspects ; Genomes ; Hemorrhagic fever ; Hemorrhagic Fever, Ebola ; Humans ; Identification and classification ; Methods ; Mice ; Molecular weight ; Nucleocapsid Proteins ; Proteins ; Replication ; RNA polymerase ; Ubiquitin ; Ubiquitin - metabolism ; Ubiquitin-proteasome system ; Ubiquitination ; Viral diseases ; Viral Regulatory and Accessory Proteins ; Virus Replication - genetics ; Viruses</subject><ispartof>PLoS biology, 2024-02, Vol.22 (2), p.e3002544</ispartof><rights>Copyright: © 2024 Rodríguez-Salazar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2024 Public Library of Science</rights><rights>2024 Rodríguez-Salazar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2024 Rodríguez-Salazar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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EBOV replication requires the activity of the viral polymerase complex, which includes the cofactor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface, and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity. Treatment with the compounds reduced replication of infectious EBOV in cells and in vivo in a mouse model. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity.</description><subject>Addition polymerization</subject><subject>Analysis</subject><subject>Animals</subject><subject>Chemical compounds</subject><subject>Covalence</subject><subject>Ebola virus</subject><subject>Ebolavirus</subject><subject>Ebolavirus - genetics</subject><subject>Ectopic expression</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Hemorrhagic fever</subject><subject>Hemorrhagic Fever, Ebola</subject><subject>Humans</subject><subject>Identification and classification</subject><subject>Methods</subject><subject>Mice</subject><subject>Molecular weight</subject><subject>Nucleocapsid Proteins</subject><subject>Proteins</subject><subject>Replication</subject><subject>RNA polymerase</subject><subject>Ubiquitin</subject><subject>Ubiquitin - metabolism</subject><subject>Ubiquitin-proteasome system</subject><subject>Ubiquitination</subject><subject>Viral diseases</subject><subject>Viral Regulatory and Accessory Proteins</subject><subject>Virus Replication - 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EBOV replication requires the activity of the viral polymerase complex, which includes the cofactor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface, and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity. Treatment with the compounds reduced replication of infectious EBOV in cells and in vivo in a mouse model. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>38422166</pmid><doi>10.1371/journal.pbio.3002544</doi><orcidid>https://orcid.org/0000-0002-5058-5444</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1545-7885 |
| ispartof | PLoS biology, 2024-02, Vol.22 (2), p.e3002544 |
| issn | 1545-7885 1544-9173 1545-7885 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central |
| subjects | Addition polymerization Analysis Animals Chemical compounds Covalence Ebola virus Ebolavirus Ebolavirus - genetics Ectopic expression Genetic aspects Genomes Hemorrhagic fever Hemorrhagic Fever, Ebola Humans Identification and classification Methods Mice Molecular weight Nucleocapsid Proteins Proteins Replication RNA polymerase Ubiquitin Ubiquitin - metabolism Ubiquitin-proteasome system Ubiquitination Viral diseases Viral Regulatory and Accessory Proteins Virus Replication - genetics Viruses |
| title | Ebola virus VP35 interacts non-covalently with ubiquitin chains to promote viral replication |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T13%3A19%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Ebola%20virus%20VP35%20interacts%20non-covalently%20with%20ubiquitin%20chains%20to%20promote%20viral%20replication&rft.jtitle=PLoS%20biology&rft.au=Rodr%C3%ADguez-Salazar,%20Carlos%20A&rft.date=2024-02-01&rft.volume=22&rft.issue=2&rft.spage=e3002544&rft.pages=e3002544-&rft.issn=1545-7885&rft.eissn=1545-7885&rft_id=info:doi/10.1371/journal.pbio.3002544&rft_dat=%3Cgale_plos_%3EA785877380%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3069178353&rft_id=info:pmid/38422166&rft_galeid=A785877380&rft_doaj_id=oai_doaj_org_article_99a4e0e8910746299e1402b8c51819c3&rfr_iscdi=true |