Functionality of redox-active crysteines is required for restriction of retroviral replication by SAMHD1
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Date
2018
Authors
Wang, Zhonghua
Bhattacharya, Akash
White, Tommy
Buffone, Cindy
McCabe, Aine
Nguyen, Laura A.
Shepard, Caitlin N.
Pardo, Sammy
Kim, Baek
Weintraub, Susan T.
Journal Title
Journal ISSN
Volume Title
Publisher
Cell Press
Abstract
SAMHD1 is a dNTP triphosphohydrolase (dNTPase)that impairs retroviral replication in a subset of non-cycling immune cells. Here we show that SAMHD1is a redox-sensitive enzyme and identify threeredox-active cysteines within the protein: C341,C350, and C522. The three cysteines reside nearone another and the allosteric nucleotide bindingsite. Mutations C341S and C522S abolish the abilityof SAMHD1 to restrict HIV replication, whereas theC350S mutant remains restriction competent. TheC522S mutation makes the protein resistant to inhibi-tion by hydrogen peroxide but has no effect onthe tetramerization-dependent dNTPase activity ofSAMHD1in vitroor on the ability of SAMHD1 todeplete cellular dNTPs. Our results reveal that enzy-matic activation of SAMHD1 via nucleotide-depen-dent tetramerization is not sufficient for the estab-lishment of the antiviral state and that retroviralrestriction depends on the ability of the protein to un-dergo redox transformations.
Description
Open access article. Creative Commons 4.0 International License (CC BY 4.0) applies
Keywords
SAMHD1 , HIV , Innate immunity , Restriction factors , dNTP , Redox signaling , Reactive oxygen species
Citation
Wang, Z., Bhattacharya, A., White, T., Buffone, C., McCabe, A., Nguyen, L. A., Shepard, C. N., Pardo, S., Kim, B., Weintraub, S. T., Demeler, B., Diaz-Griffero, F., & Ivanov, D. N. (2018). Functionality of redox-active crysteines is required for restriction of retroviral replication by SAMHD1. Cell Reports, 24(4), 815-823. https://doi.org/10.1016/j.celrep.2018.06.090