SAMHD1

The restriction factor SAMHD1 prevents HIV-1 infection of macrophages, dendritic cells, and resting T cells (Baldauf et al., 2012; Hrecka et al., 2011; Laguette et al., 2011). Our investigations revealed that SAMHD1 is regulated by phosphorylation of T592(White et al., 2013a; 2013b)(Fig. 5). The unphosphorylated form of SAMHD1 potently blocks HIV-1 infection. By contrast the phosphorylated form does not affect HIV-1 infection. These investigations suggested that the ability of SAMHD1 to block HIV-1 infection can be modulated. To this end, we are currently investigating in human primary cells the regulation of phosphorylation by different cytokines. We recently found that SAMHD1 is S-glutathionylated, and that this post-translational modification is essential for the ability of SAMHD1 to block HIV-1 infection. We are currently investigating the contribution of SAMHD1 S-glutathionylation to restriction. Although we have performed extensive biochemical and cellular characterization of SAMHD1(Brandariz-Nuñez et al., 2013; 2012; Ryoo et al., 2014; St Gelais et al., 2014; Welbourn et al., 2012; White et al., 2013b; 2014), we have not explored the role of SAMHD1 in immunity. Efficient lentiviral infection of macrophages in old world monkeys correlates with a strong adaptive immunity (Schaller et al., 2012).

Figure 5. Regulation of SAMHD1 anti-HIV-1 activity by phosphorylation. Our investigations revealed that phosphorylation of SAMHD1 at T592 modulates the ability of this restriction factor to block HIV-1 infection of macrophages.

We are currently testing the hypothesis that SAMHD1 is involved in adaptive immunity. To this end, we will study adaptive immunity in the SAMHD1 knockout mice by testing antibody response, and the ability of the mice to prevent the growth of diverse pathogens. We will initially test pathogens that are known to be inhibited by SAMHD1, such as HSV-1/2(Kim et al., 2013) and mycobacterium tuberculosis(our unpublished preliminary studies). These investigations will help us understand the role of SAMHD1 in the immune system.

Wang Z, Bhattacharya A, Villacorta J, Diaz-Griffero F, Ivanon DN. Allosteric activation of SAMHD1 protein by deoxynucleotide triphosphate (dNTP)-dependent tetramerization requires dNTP concentration that are similar to dNTP concentrations observed in cycling T cells. J. Biol. Chem. 2016 Oct; 291(41): 21407-21413. DOI:10.1074/jbc.C116.751446

Bhattacharya A, Wang Z, White T, Buffone C, Nguyen LA, Shepard CN, Kim B, Demeler B, Diaz-Griffero F, Ivanov DN. Effects of T592 phosphomimetic mutations on tetramer stability and dNTPase activity of SAMHD1 can not explain the retroviral restriction defect. Sci Rep. 2016 Aug; 6: 31353. DOI:10.1038/srep31353

White TE, Brandariz-Nuñez A, Han K, Sawyer SL, Kim B, Diaz-Griffero F. Modulation of LINE-1 retrotransposition by a human SAMHD1 polymorphism. Virology Reports. 2016 Dec; 6: 53-60. DOI: 10.1016/j.virep.2016.06.001

Hollenbaugh JA, Tao S, Lenzi GM, Ryu S, Kim DH, Diaz-Griffero F, Schinazi RF, Kim B. dNTP pool modulation dynamics by SAMHD1 protein in monocyte-derived macrophages. Retrovirology. 2014 Aug 27;11:63. doi: 10.1186/s12977-014-0063-2. PubMed PMID: 25158827; PubMed Central PMCID: PMC4161909.

Ryoo J, Choi J, Oh C, Kim S, Seo M, Kim SY, Seo D, Kim J, White TE, Brandariz-Nuñez A, Diaz-Griffero F, Yun CH, Hollenbaugh JA, Kim B, Baek D, Ahn K. The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med. 2014 Aug;20(8):936-41. doi: 10.1038/nm.3626. Epub 2014 Jul 20. PubMed PMID: 25038827; PubMed Central PMCID: PMC4318684.

White TE, Brandariz-Nuñez A, Valle-Casuso JC, Knowlton C, Kim B, Sawyer SL, Diaz-Griffero F. Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility. Virology. 2014 Jul;460-461:34-44. doi: 10.1016/j.virol.2014.04.023. Epub 2014 May 29. PubMed PMID: 25010268; PubMed Central PMCID: PMC4101048.

St Gelais C, de Silva S, Hach JC, White TE, Diaz-Griffero F, Yount JS, Wu L. Identification of cellular proteins interacting with the retroviral restriction factor SAMHD1. J Virol. 2014 May;88(10):5834-44. doi: 10.1128/JVI.00155-14. Epub 2014 Mar 12. Erratum in: J Virol. 2014 Jul;88(13):7689. PubMed PMID: 24623419; PubMed Central PMCID: PMC4019113.

Kim ET, White TE, Brandariz-Núñez A, Diaz-Griffero F, Weitzman MD. SAMHD1 restricts herpes simplex virus 1 in macrophages by limiting DNA replication. J Virol. 2013 Dec;87(23):12949-56. doi: 10.1128/JVI.02291-13. Epub 2013 Sep 25. PubMed PMID: 24067963; PubMed Central PMCID: PMC3838123.

Brandariz-Nuñez A, Valle-Casuso JC, White TE, Nguyen L, Bhattacharya A, Wang Z, Demeler B, Amie S, Knowlton C, Kim B, Ivanov DN, Diaz-Griffero F. Contribution of oligomerization to the anti-HIV-1 properties of SAMHD1. Retrovirology. 2013 Nov 12;10:131. doi: 10.1186/1742-4690-10-131. PubMed PMID: 24219908; PubMed Central PMCID: PMC3882887.

White TE, Brandariz-Nuñez A, Valle-Casuso JC, Amie S, Nguyen LA, Kim B, Tuzova M, Diaz-Griffero F. The retroviral restriction ability of SAMHD1, but not its deoxynucleotide triphosphohydrolase activity, is regulated by phosphorylation. Cell Host Microbe. 2013 Apr 17;13(4):441-51. doi: 10.1016/j.chom.2013.03.005. PubMed PMID: 23601106; PubMed Central PMCID: PMC3864637.

White TE, Brandariz-Nuñez A, Valle-Casuso JC, Amie S, Nguyen L, Kim B, Brojatsch J, Diaz-Griffero F. Contribution of SAM and HD domains to retroviral restriction mediated by human SAMHD1. Virology. 2013 Feb 5;436(1):81-90. doi: 10.1016/j.virol.2012.10.029. Epub 2012 Nov 13. PubMed PMID: 23158101; PubMed Central PMCID: PMC3767443.

Welbourn S, Miyagi E, White TE, Diaz-Griffero F, Strebel K. Identification and characterization of naturally occurring splice variants of SAMHD1. Retrovirology. 2012 Oct 23;9:86. doi: 10.1186/1742-4690-9-86. PubMed PMID: 23092512; PubMed Central PMCID: PMC3503569.

Brandariz-Nuñez A, Valle-Casuso JC, White TE, Laguette N, Benkirane M, Brojatsch J, Diaz-Griffero F. Role of SAMHD1 nuclear localization in restriction of HIV-1 and SIVmac. Retrovirology. 2012 Jun 12;9:49. doi: 10.1186/1742-4690-9-49. PubMed PMID: 22691373; PubMed Central PMCID: PMC3410799.