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 E Weintraub, Borries Demeler, Felipe Diaz-Griffero, Dmitri N Ivanov

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)815-823
Number of pages9
JournalCell Reports
Volume24
Issue number4
DOIs
StatePublished - Jul 24 2018

Fingerprint

Oxidation-Reduction
Cysteine
Nucleotides
Mutation
Proteins
Hydrogen Peroxide
Antiviral Agents
Chemical activation
Binding Sites
HIV
Enzymes
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1. / Wang, Zhonghua; Bhattacharya, Akash; White, Tommy; Buffone, Cindy; McCabe, Aine; Nguyen, Laura A.; Shepard, Caitlin N.; Pardo, Sammy; Kim, Baek; Weintraub, Susan E; Demeler, Borries; Diaz-Griffero, Felipe; Ivanov, Dmitri N.

In: Cell Reports, Vol. 24, No. 4, 24.07.2018, p. 815-823.

Research output: Contribution to journalArticle

Wang, Z, Bhattacharya, A, White, T, Buffone, C, McCabe, A, Nguyen, LA, Shepard, CN, Pardo, S, Kim, B, Weintraub, SE, Demeler, B, Diaz-Griffero, F & Ivanov, DN 2018, 'Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1', Cell Reports, vol. 24, no. 4, pp. 815-823. https://doi.org/10.1016/j.celrep.2018.06.090
Wang, Zhonghua ; Bhattacharya, Akash ; White, Tommy ; Buffone, Cindy ; McCabe, Aine ; Nguyen, Laura A. ; Shepard, Caitlin N. ; Pardo, Sammy ; Kim, Baek ; Weintraub, Susan E ; Demeler, Borries ; Diaz-Griffero, Felipe ; Ivanov, Dmitri N. / Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1. In: Cell Reports. 2018 ; Vol. 24, No. 4. pp. 815-823.
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