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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2022
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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. |
format | Online Article Text |
id | pubmed-9623979 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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