The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch

Christopher H. Mauney; Leann C. Rogers; Reuben S. Harris; Larry W. Daniel; Nelmi O. Devarie-Baez; Hanzhi Wu; Cristina M. Furdui; Leslie B. Poole; Fred W. Perrino; Thomas Hollis

doi:10.1089/ars.2016.6888

The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch

Christopher H. Mauney, Leann C. Rogers, Reuben S. Harris, Larry W. Daniel, Nelmi O. Devarie-Baez, Hanzhi Wu, Cristina M. Furdui, Leslie B. Poole, Fred W. Perrino, Thomas Hollis

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

30 Scopus citations

Abstract

Aims: Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. Results: Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools. We demonstrate that the redox state of SAMHD1 regulates its catalytic activity. We have identified three cysteine residues that constitute an intrachain disulfide bond "redox switch" that reversibly inhibits protein tetramerization and catalysis. We show that proliferative signals lead to SAMHD1 oxidation in cells and oxidized SAMHD1 is localized outside of the nucleus. Innovation and Conclusions: SAMHD1 catalytic activity is reversibly regulated by protein oxidation. These data identify a previously unknown mechanism for regulation of nucleotide metabolism by SAMHD1. Antioxid. Redox Signal. 27, 1317-1331.

Original language	English (US)
Pages (from-to)	1317-1331
Number of pages	15
Journal	Antioxidants and Redox Signaling
Volume	27
Issue number	16
DOIs	https://doi.org/10.1089/ars.2016.6888
State	Published - Dec 1 2017
Externally published	Yes

Keywords

Aicardi-Goutieres syndrome
HIV restriction
SAMHD1
enzyme catalysis
protein oxidation
redox switch

ASJC Scopus subject areas

Biochemistry
Physiology
Molecular Biology
Clinical Biochemistry
Cell Biology

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10.1089/ars.2016.6888

Cite this

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title = "The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch",

abstract = "Aims: Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. Results: Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools. We demonstrate that the redox state of SAMHD1 regulates its catalytic activity. We have identified three cysteine residues that constitute an intrachain disulfide bond {"}redox switch{"} that reversibly inhibits protein tetramerization and catalysis. We show that proliferative signals lead to SAMHD1 oxidation in cells and oxidized SAMHD1 is localized outside of the nucleus. Innovation and Conclusions: SAMHD1 catalytic activity is reversibly regulated by protein oxidation. These data identify a previously unknown mechanism for regulation of nucleotide metabolism by SAMHD1. Antioxid. Redox Signal. 27, 1317-1331.",

keywords = "Aicardi-Goutieres syndrome, HIV restriction, SAMHD1, enzyme catalysis, protein oxidation, redox switch",

author = "Mauney, {Christopher H.} and Rogers, {Leann C.} and Harris, {Reuben S.} and Daniel, {Larry W.} and Devarie-Baez, {Nelmi O.} and Hanzhi Wu and Furdui, {Cristina M.} and Poole, {Leslie B.} and Perrino, {Fred W.} and Thomas Hollis",

note = "Funding Information: We thank Dr. Jingyun Lee and the staff of the Metabo-lomics and Proteomics Shared Resource of the Wake Forest School of Medicine for their assistance in the performance and analysis of mass spectrometry experiments, and Amy Molan and Michael Carpenter for comments on the article. This work has been supported through funding from the NIH (RO1 GM108827 to T.H., RO1 CA142838 to L.W.D., R01 GM06692 to F.W.P., and R33 CA177461 to L.B.P., and T32 GM095440 support for C.H.M.), Alliance for Lupus Research to F.W.P., and the Comprehensive Cancer Center of Wake Forest University National Cancer Institute Cancer Center Support Grant P30CA012197. R.S.H. is an Investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} Copyright 2017, Mary Ann Liebert, Inc. 2017.",

year = "2017",

month = dec,

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doi = "10.1089/ars.2016.6888",

language = "English (US)",

volume = "27",

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T1 - The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch

AU - Mauney, Christopher H.

AU - Rogers, Leann C.

AU - Harris, Reuben S.

AU - Daniel, Larry W.

AU - Devarie-Baez, Nelmi O.

AU - Wu, Hanzhi

AU - Furdui, Cristina M.

AU - Poole, Leslie B.

AU - Perrino, Fred W.

AU - Hollis, Thomas

N1 - Funding Information: We thank Dr. Jingyun Lee and the staff of the Metabo-lomics and Proteomics Shared Resource of the Wake Forest School of Medicine for their assistance in the performance and analysis of mass spectrometry experiments, and Amy Molan and Michael Carpenter for comments on the article. This work has been supported through funding from the NIH (RO1 GM108827 to T.H., RO1 CA142838 to L.W.D., R01 GM06692 to F.W.P., and R33 CA177461 to L.B.P., and T32 GM095440 support for C.H.M.), Alliance for Lupus Research to F.W.P., and the Comprehensive Cancer Center of Wake Forest University National Cancer Institute Cancer Center Support Grant P30CA012197. R.S.H. is an Investigator of the Howard Hughes Medical Institute. Publisher Copyright: © Copyright 2017, Mary Ann Liebert, Inc. 2017.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Aims: Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. Results: Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools. We demonstrate that the redox state of SAMHD1 regulates its catalytic activity. We have identified three cysteine residues that constitute an intrachain disulfide bond "redox switch" that reversibly inhibits protein tetramerization and catalysis. We show that proliferative signals lead to SAMHD1 oxidation in cells and oxidized SAMHD1 is localized outside of the nucleus. Innovation and Conclusions: SAMHD1 catalytic activity is reversibly regulated by protein oxidation. These data identify a previously unknown mechanism for regulation of nucleotide metabolism by SAMHD1. Antioxid. Redox Signal. 27, 1317-1331.

AB - Aims: Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. Results: Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools. We demonstrate that the redox state of SAMHD1 regulates its catalytic activity. We have identified three cysteine residues that constitute an intrachain disulfide bond "redox switch" that reversibly inhibits protein tetramerization and catalysis. We show that proliferative signals lead to SAMHD1 oxidation in cells and oxidized SAMHD1 is localized outside of the nucleus. Innovation and Conclusions: SAMHD1 catalytic activity is reversibly regulated by protein oxidation. These data identify a previously unknown mechanism for regulation of nucleotide metabolism by SAMHD1. Antioxid. Redox Signal. 27, 1317-1331.

KW - Aicardi-Goutieres syndrome

KW - HIV restriction

KW - SAMHD1

KW - enzyme catalysis

KW - protein oxidation

KW - redox switch

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EP - 1331

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

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ER -

The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch

Abstract

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