Sirtuins Are Evolutionarily Conserved Viral Restriction Factors

ABSTRACT The seven human sirtuins are a family of ubiquitously expressed and evolutionarily conserved NAD+-dependent deacylases/mono-ADP ribosyltransferases that regulate numerous cellular and organismal functions, including metabolism, cell cycle, and longevity. Here, we report the discovery that a...

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Autores principales:	Emre Koyuncu, Hanna G. Budayeva, Yana V. Miteva, Dante P. Ricci, Thomas J. Silhavy, Thomas Shenk, Ileana M. Cristea
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b9ea76d5d00f400d8e2b497edc864f67
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spelling	oai:doaj.org-article:b9ea76d5d00f400d8e2b497edc864f672021-11-15T15:47:03ZSirtuins Are Evolutionarily Conserved Viral Restriction Factors10.1128/mBio.02249-142150-7511https://doaj.org/article/b9ea76d5d00f400d8e2b497edc864f672014-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02249-14https://doaj.org/toc/2150-7511ABSTRACT The seven human sirtuins are a family of ubiquitously expressed and evolutionarily conserved NAD+-dependent deacylases/mono-ADP ribosyltransferases that regulate numerous cellular and organismal functions, including metabolism, cell cycle, and longevity. Here, we report the discovery that all seven sirtuins have broad-range antiviral properties. We demonstrate that small interfering RNA (siRNA)-mediated knockdown of individual sirtuins and drug-mediated inhibition of sirtuin enzymatic activity increase the production of virus progeny in infected human cells. This impact on virus growth is observed for both DNA and RNA viruses. Importantly, sirtuin-activating drugs inhibit the replication of diverse viruses, as we demonstrate for human cytomegalovirus, a slowly replicating DNA virus, and influenza A (H1N1) virus, an RNA virus that multiplies rapidly. Furthermore, sirtuin defense functions are evolutionarily conserved, since CobB, the sirtuin homologue in Escherichia coli, protects against bacteriophages. Altogether, our findings establish sirtuins as broad-spectrum and evolutionarily conserved components of the immune defense system, providing a framework for elucidating a new set of host cell defense mechanisms and developing sirtuin modulators with antiviral activity. IMPORTANCE We live in a sea of viruses, some of which are human pathogens. These pathogenic viruses exhibit numerous differences: DNA or RNA genomes, enveloped or naked virions, nuclear or cytoplasmic replication, diverse disease symptoms, etc. Most antiviral drugs target specific viral proteins. Consequently, they often work for only one virus, and their efficacy can be compromised by the rapid evolution of resistant variants. There is a need for the identification of host proteins with broad-spectrum antiviral functions, which provide effective targets for therapeutic treatments that limit the evolution of viral resistance. Here, we report that sirtuins present such an opportunity for the development of broad-spectrum antiviral treatments, since our findings highlight these enzymes as ancient defense factors that protect against a variety of viral pathogens.Emre KoyuncuHanna G. BudayevaYana V. MitevaDante P. RicciThomas J. SilhavyThomas ShenkIleana M. CristeaAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 6 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Emre Koyuncu Hanna G. Budayeva Yana V. Miteva Dante P. Ricci Thomas J. Silhavy Thomas Shenk Ileana M. Cristea Sirtuins Are Evolutionarily Conserved Viral Restriction Factors
description	ABSTRACT The seven human sirtuins are a family of ubiquitously expressed and evolutionarily conserved NAD+-dependent deacylases/mono-ADP ribosyltransferases that regulate numerous cellular and organismal functions, including metabolism, cell cycle, and longevity. Here, we report the discovery that all seven sirtuins have broad-range antiviral properties. We demonstrate that small interfering RNA (siRNA)-mediated knockdown of individual sirtuins and drug-mediated inhibition of sirtuin enzymatic activity increase the production of virus progeny in infected human cells. This impact on virus growth is observed for both DNA and RNA viruses. Importantly, sirtuin-activating drugs inhibit the replication of diverse viruses, as we demonstrate for human cytomegalovirus, a slowly replicating DNA virus, and influenza A (H1N1) virus, an RNA virus that multiplies rapidly. Furthermore, sirtuin defense functions are evolutionarily conserved, since CobB, the sirtuin homologue in Escherichia coli, protects against bacteriophages. Altogether, our findings establish sirtuins as broad-spectrum and evolutionarily conserved components of the immune defense system, providing a framework for elucidating a new set of host cell defense mechanisms and developing sirtuin modulators with antiviral activity. IMPORTANCE We live in a sea of viruses, some of which are human pathogens. These pathogenic viruses exhibit numerous differences: DNA or RNA genomes, enveloped or naked virions, nuclear or cytoplasmic replication, diverse disease symptoms, etc. Most antiviral drugs target specific viral proteins. Consequently, they often work for only one virus, and their efficacy can be compromised by the rapid evolution of resistant variants. There is a need for the identification of host proteins with broad-spectrum antiviral functions, which provide effective targets for therapeutic treatments that limit the evolution of viral resistance. Here, we report that sirtuins present such an opportunity for the development of broad-spectrum antiviral treatments, since our findings highlight these enzymes as ancient defense factors that protect against a variety of viral pathogens.
format	article
author	Emre Koyuncu Hanna G. Budayeva Yana V. Miteva Dante P. Ricci Thomas J. Silhavy Thomas Shenk Ileana M. Cristea
author_facet	Emre Koyuncu Hanna G. Budayeva Yana V. Miteva Dante P. Ricci Thomas J. Silhavy Thomas Shenk Ileana M. Cristea
author_sort	Emre Koyuncu
title	Sirtuins Are Evolutionarily Conserved Viral Restriction Factors
title_short	Sirtuins Are Evolutionarily Conserved Viral Restriction Factors
title_full	Sirtuins Are Evolutionarily Conserved Viral Restriction Factors
title_fullStr	Sirtuins Are Evolutionarily Conserved Viral Restriction Factors
title_full_unstemmed	Sirtuins Are Evolutionarily Conserved Viral Restriction Factors
title_sort	sirtuins are evolutionarily conserved viral restriction factors
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/b9ea76d5d00f400d8e2b497edc864f67
work_keys_str_mv	AT emrekoyuncu sirtuinsareevolutionarilyconservedviralrestrictionfactors AT hannagbudayeva sirtuinsareevolutionarilyconservedviralrestrictionfactors AT yanavmiteva sirtuinsareevolutionarilyconservedviralrestrictionfactors AT dantepricci sirtuinsareevolutionarilyconservedviralrestrictionfactors AT thomasjsilhavy sirtuinsareevolutionarilyconservedviralrestrictionfactors AT thomasshenk sirtuinsareevolutionarilyconservedviralrestrictionfactors AT ileanamcristea sirtuinsareevolutionarilyconservedviralrestrictionfactors
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Sirtuins Are Evolutionarily Conserved Viral Restriction Factors

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