Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1

Zhonghua Wang; Akash Bhattacharya; Tommy White; Cindy Buffone; Aine McCabe; Laura A. Nguyen; Caitlin N. Shepard; Sammy Pardo; Baek Kim; Susan T. Weintraub; Borries Demeler; Felipe Diaz-Griffero; Dmitri N. Ivanov

doi:10.1016/j.celrep.2018.06.090

Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1

Zhonghua Wang, Akash Bhattacharya, Tommy White, Cindy Buffone, Aine McCabe, Laura A. Nguyen, Caitlin N. Shepard, Sammy Pardo, Baek Kim, Susan T. Weintraub, Borries Demeler, Felipe Diaz-Griffero, Dmitri N. Ivanov

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

SAMHD1 is a dNTP triphosphohydrolase (dNTPase) that impairs retroviral replication in a subset of non-cycling immune cells. Here we show that SAMHD1 is a redox-sensitive enzyme and identify three redox-active cysteines within the protein: C341, C350, and C522. The three cysteines reside near one another and the allosteric nucleotide binding site. Mutations C341S and C522S abolish the ability of SAMHD1 to restrict HIV replication, whereas the C350S mutant remains restriction competent. The C522S mutation makes the protein resistant to inhibition by hydrogen peroxide but has no effect on the tetramerization-dependent dNTPase activity of SAMHD1 in vitro or on the ability of SAMHD1 to deplete cellular dNTPs. Our results reveal that enzymatic activation of SAMHD1 via nucleotide-dependent tetramerization is not sufficient for the establishment of the antiviral state and that retroviral restriction depends on the ability of the protein to undergo redox transformations.

Original language	English (US)
Pages (from-to)	815-823
Number of pages	9
Journal	Cell Reports
Volume	24
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2018.06.090
State	Published - Jul 24 2018

Keywords

HIV
SAMHD1
dNTP
innate immunity
reactive oxygen species
redox signaling
restriction factors
retroviruses

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2018.06.090

Cite this

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title = "Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1",

abstract = "SAMHD1 is a dNTP triphosphohydrolase (dNTPase) that impairs retroviral replication in a subset of non-cycling immune cells. Here we show that SAMHD1 is a redox-sensitive enzyme and identify three redox-active cysteines within the protein: C341, C350, and C522. The three cysteines reside near one another and the allosteric nucleotide binding site. Mutations C341S and C522S abolish the ability of SAMHD1 to restrict HIV replication, whereas the C350S mutant remains restriction competent. The C522S mutation makes the protein resistant to inhibition by hydrogen peroxide but has no effect on the tetramerization-dependent dNTPase activity of SAMHD1 in vitro or on the ability of SAMHD1 to deplete cellular dNTPs. Our results reveal that enzymatic activation of SAMHD1 via nucleotide-dependent tetramerization is not sufficient for the establishment of the antiviral state and that retroviral restriction depends on the ability of the protein to undergo redox transformations.",

keywords = "HIV, SAMHD1, dNTP, innate immunity, reactive oxygen species, redox signaling, restriction factors, retroviruses",

author = "Zhonghua Wang and Akash Bhattacharya and Tommy White and Cindy Buffone and Aine McCabe and Nguyen, {Laura A.} and Shepard, {Caitlin N.} and Sammy Pardo and Baek Kim and Weintraub, {Susan T.} and Borries Demeler and Felipe Diaz-Griffero and Ivanov, {Dmitri N.}",

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AU - Wang, Zhonghua

AU - Bhattacharya, Akash

AU - White, Tommy

AU - Buffone, Cindy

AU - McCabe, Aine

AU - Nguyen, Laura A.

AU - Shepard, Caitlin N.

AU - Pardo, Sammy

AU - Kim, Baek

AU - Weintraub, Susan T.

AU - Demeler, Borries

AU - Diaz-Griffero, Felipe

AU - Ivanov, Dmitri N.

PY - 2018/7/24

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N2 - SAMHD1 is a dNTP triphosphohydrolase (dNTPase) that impairs retroviral replication in a subset of non-cycling immune cells. Here we show that SAMHD1 is a redox-sensitive enzyme and identify three redox-active cysteines within the protein: C341, C350, and C522. The three cysteines reside near one another and the allosteric nucleotide binding site. Mutations C341S and C522S abolish the ability of SAMHD1 to restrict HIV replication, whereas the C350S mutant remains restriction competent. The C522S mutation makes the protein resistant to inhibition by hydrogen peroxide but has no effect on the tetramerization-dependent dNTPase activity of SAMHD1 in vitro or on the ability of SAMHD1 to deplete cellular dNTPs. Our results reveal that enzymatic activation of SAMHD1 via nucleotide-dependent tetramerization is not sufficient for the establishment of the antiviral state and that retroviral restriction depends on the ability of the protein to undergo redox transformations.

AB - SAMHD1 is a dNTP triphosphohydrolase (dNTPase) that impairs retroviral replication in a subset of non-cycling immune cells. Here we show that SAMHD1 is a redox-sensitive enzyme and identify three redox-active cysteines within the protein: C341, C350, and C522. The three cysteines reside near one another and the allosteric nucleotide binding site. Mutations C341S and C522S abolish the ability of SAMHD1 to restrict HIV replication, whereas the C350S mutant remains restriction competent. The C522S mutation makes the protein resistant to inhibition by hydrogen peroxide but has no effect on the tetramerization-dependent dNTPase activity of SAMHD1 in vitro or on the ability of SAMHD1 to deplete cellular dNTPs. Our results reveal that enzymatic activation of SAMHD1 via nucleotide-dependent tetramerization is not sufficient for the establishment of the antiviral state and that retroviral restriction depends on the ability of the protein to undergo redox transformations.

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KW - SAMHD1

KW - dNTP

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KW - reactive oxygen species

KW - redox signaling

KW - restriction factors

KW - retroviruses

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Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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