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Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality

Viruses co-opt host proteins to carry out their lifecycle. Repurposed host proteins may thus become functionally compromised; a situation analogous to a loss-of-function mutation. We term such host proteins as viral-induced hypomorphs. Cells bearing cancer driver loss-of-function mutations have succ...

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Autores principales: Navare, Arti T., Mast, Fred D., Olivier, Jean Paul, Bertomeu, Thierry, Neal, Maxwell L., Carpp, Lindsay N., Kaushansky, Alexis, Coulombe-Huntington, Jasmin, Tyers, Mike, Aitchison, John D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9623979/
https://www.ncbi.nlm.nih.gov/pubmed/36305789
http://dx.doi.org/10.1083/jcb.202011050
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author Navare, Arti T.
Mast, Fred D.
Olivier, Jean Paul
Bertomeu, Thierry
Neal, Maxwell L.
Carpp, Lindsay N.
Kaushansky, Alexis
Coulombe-Huntington, Jasmin
Tyers, Mike
Aitchison, John D.
author_facet Navare, Arti T.
Mast, Fred D.
Olivier, Jean Paul
Bertomeu, Thierry
Neal, Maxwell L.
Carpp, Lindsay N.
Kaushansky, Alexis
Coulombe-Huntington, Jasmin
Tyers, Mike
Aitchison, John D.
author_sort Navare, Arti T.
collection PubMed
description Viruses co-opt host proteins to carry out their lifecycle. Repurposed host proteins may thus become functionally compromised; a situation analogous to a loss-of-function mutation. We term such host proteins as viral-induced hypomorphs. Cells bearing cancer driver loss-of-function mutations have successfully been targeted with drugs perturbing proteins encoded by the synthetic lethal (SL) partners of cancer-specific mutations. Similarly, SL interactions of viral-induced hypomorphs can potentially be targeted as host-based antiviral therapeutics. Here, we use GBF1, which supports the infection of many RNA viruses, as a proof-of-concept. GBF1 becomes a hypomorph upon interaction with the poliovirus protein 3A. Screening for SL partners of GBF1 revealed ARF1 as the top hit, disruption of which selectively killed cells that synthesize 3A alone or in the context of a poliovirus replicon. Thus, viral protein interactions can induce hypomorphs that render host cells selectively vulnerable to perturbations that leave uninfected cells otherwise unscathed. Exploiting viral-induced vulnerabilities could lead to broad-spectrum antivirals for many viruses, including SARS-CoV-2.
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spelling pubmed-96239792022-11-02 Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality Navare, Arti T. Mast, Fred D. Olivier, Jean Paul Bertomeu, Thierry Neal, Maxwell L. Carpp, Lindsay N. Kaushansky, Alexis Coulombe-Huntington, Jasmin Tyers, Mike Aitchison, John D. J Cell Biol Report Viruses co-opt host proteins to carry out their lifecycle. Repurposed host proteins may thus become functionally compromised; a situation analogous to a loss-of-function mutation. We term such host proteins as viral-induced hypomorphs. Cells bearing cancer driver loss-of-function mutations have successfully been targeted with drugs perturbing proteins encoded by the synthetic lethal (SL) partners of cancer-specific mutations. Similarly, SL interactions of viral-induced hypomorphs can potentially be targeted as host-based antiviral therapeutics. Here, we use GBF1, which supports the infection of many RNA viruses, as a proof-of-concept. GBF1 becomes a hypomorph upon interaction with the poliovirus protein 3A. Screening for SL partners of GBF1 revealed ARF1 as the top hit, disruption of which selectively killed cells that synthesize 3A alone or in the context of a poliovirus replicon. Thus, viral protein interactions can induce hypomorphs that render host cells selectively vulnerable to perturbations that leave uninfected cells otherwise unscathed. Exploiting viral-induced vulnerabilities could lead to broad-spectrum antivirals for many viruses, including SARS-CoV-2. Rockefeller University Press 2022-10-28 /pmc/articles/PMC9623979/ /pubmed/36305789 http://dx.doi.org/10.1083/jcb.202011050 Text en © 2022 Navare et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Report
Navare, Arti T.
Mast, Fred D.
Olivier, Jean Paul
Bertomeu, Thierry
Neal, Maxwell L.
Carpp, Lindsay N.
Kaushansky, Alexis
Coulombe-Huntington, Jasmin
Tyers, Mike
Aitchison, John D.
Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality
title Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality
title_full Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality
title_fullStr Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality
title_full_unstemmed Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality
title_short Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality
title_sort viral protein engagement of gbf1 induces host cell vulnerability through synthetic lethality
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9623979/
https://www.ncbi.nlm.nih.gov/pubmed/36305789
http://dx.doi.org/10.1083/jcb.202011050
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