GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration

Abstract GCN2 is a serine/threonine kinase involved in cellular stress response related to amino acid starvation. Previously, we showed that GCN2 interacts with HIV-1 integrase and is activated during HIV-1 infection. Herein, we identified HIV-1 integrase as a previously unknown substrate of GCN2 in...

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Autores principales:	A. Jaspart, C. Calmels, O. Cosnefroy, P. Bellecave, P. Pinson, S. Claverol, V. Guyonnet-Dupérat, B. Dartigues, M. S. Benleulmi, E. Mauro, P. A. Gretteau, V. Parissi, M. Métifiot, M. L. Andreola
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/998828727f8e4d62a97fb16cfbfb7dc4
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spelling	oai:doaj.org-article:998828727f8e4d62a97fb16cfbfb7dc42021-12-02T16:06:18ZGCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration10.1038/s41598-017-02276-02045-2322https://doaj.org/article/998828727f8e4d62a97fb16cfbfb7dc42017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02276-0https://doaj.org/toc/2045-2322Abstract GCN2 is a serine/threonine kinase involved in cellular stress response related to amino acid starvation. Previously, we showed that GCN2 interacts with HIV-1 integrase and is activated during HIV-1 infection. Herein, we identified HIV-1 integrase as a previously unknown substrate of GCN2 in vitro with a major site of phosphorylation at residue S255 located in the C-terminal domain of HIV-1 integrase. The underlying mechanism was investigated and it appeared that the integrase active site was required in order for GCN2 to target the integrase residue S255. Moreover, various integrases from other retroviruses (e.g. MLV, ASV) were also recognized as a substrate by GCN2. In cells, HIV-1 lentiviral particles harboring mutation at integrase position 255 were affected in their replication. Preventing phosphorylation resulted in an increase in infectivity that correlated with an increase in viral DNA integration. Infectivity of MLV was also higher in cells knocked-out for GCN2 suggesting a conserved mechanism to control viral replication. Altogether, our data suggest that GCN2 may constitute a general guardian of genome stability by regulating foreign DNA integration and as such be part of the antiviral armamentarium of the cell.A. JaspartC. CalmelsO. CosnefroyP. BellecaveP. PinsonS. ClaverolV. Guyonnet-DupératB. DartiguesM. S. BenleulmiE. MauroP. A. GretteauV. ParissiM. MétifiotM. L. AndreolaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q A. Jaspart C. Calmels O. Cosnefroy P. Bellecave P. Pinson S. Claverol V. Guyonnet-Dupérat B. Dartigues M. S. Benleulmi E. Mauro P. A. Gretteau V. Parissi M. Métifiot M. L. Andreola GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration
description	Abstract GCN2 is a serine/threonine kinase involved in cellular stress response related to amino acid starvation. Previously, we showed that GCN2 interacts with HIV-1 integrase and is activated during HIV-1 infection. Herein, we identified HIV-1 integrase as a previously unknown substrate of GCN2 in vitro with a major site of phosphorylation at residue S255 located in the C-terminal domain of HIV-1 integrase. The underlying mechanism was investigated and it appeared that the integrase active site was required in order for GCN2 to target the integrase residue S255. Moreover, various integrases from other retroviruses (e.g. MLV, ASV) were also recognized as a substrate by GCN2. In cells, HIV-1 lentiviral particles harboring mutation at integrase position 255 were affected in their replication. Preventing phosphorylation resulted in an increase in infectivity that correlated with an increase in viral DNA integration. Infectivity of MLV was also higher in cells knocked-out for GCN2 suggesting a conserved mechanism to control viral replication. Altogether, our data suggest that GCN2 may constitute a general guardian of genome stability by regulating foreign DNA integration and as such be part of the antiviral armamentarium of the cell.
format	article
author	A. Jaspart C. Calmels O. Cosnefroy P. Bellecave P. Pinson S. Claverol V. Guyonnet-Dupérat B. Dartigues M. S. Benleulmi E. Mauro P. A. Gretteau V. Parissi M. Métifiot M. L. Andreola
author_facet	A. Jaspart C. Calmels O. Cosnefroy P. Bellecave P. Pinson S. Claverol V. Guyonnet-Dupérat B. Dartigues M. S. Benleulmi E. Mauro P. A. Gretteau V. Parissi M. Métifiot M. L. Andreola
author_sort	A. Jaspart
title	GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration
title_short	GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration
title_full	GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration
title_fullStr	GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration
title_full_unstemmed	GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration
title_sort	gcn2 phosphorylates hiv-1 integrase and decreases hiv-1 replication by limiting viral integration
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/998828727f8e4d62a97fb16cfbfb7dc4
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GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration

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