@article{839e0e3e3ebc418f9074d21d7fd67d59,
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.}",
note = "Funding Information: This study was supported in part by NIH R01 AI104476 (to D.N.I.), NIH R01 GM123540 (to F.D.-G.), NIH AI136581 and GM104198 (to B.K.), NIH GM120600 and NSF ACI-1339649 (to B.D.), NIH 1S10RR025111-01 (to S.T.W.), and Voelcker Fund Young Investigator Award (to D.N.I.). The UltraScan software development is supported by NIH GM120600 and NSF ACI-1339649 (to B.D.). Data analysis of AUC data was supported by XSEDE allocation grant MCB070039 (to B.D.). The Institutional Core Facilities at the UT Health Science Center at San Antonio are supported in part as shared resources (NMR, AUC, and MS) of NIH P30 CA054174 to the Mays Cancer Center-UT Health San Antonio. Funding Information: This study was supported in part by NIH R01 AI104476 (to D.N.I.), NIH R01 GM123540 (to F.D.-G.), NIH AI136581 and GM104198 (to B.K.), NIH GM120600 and NSF ACI-1339649 (to B.D.), NIH 1S10RR025111-01 (to S.T.W.), and Voelcker Fund Young Investigator Award (to D.N.I.). The UltraScan software development is supported by NIH GM120600 and NSF ACI-1339649 (to B.D.). Data analysis of AUC data was supported by XSEDE allocation grant MCB070039 (to B.D.). The Institutional Core Facilities at the UT Health Science Center at San Antonio are supported in part as shared resources (NMR, AUC, and MS) of NIH P30 CA054174 to the Mays Cancer Center-UT Health San Antonio. Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = jul,
day = "24",
doi = "10.1016/j.celrep.2018.06.090",
language = "English (US)",
volume = "24",
pages = "815--823",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}
