The Retroviral Restriction Ability of SAMHD1, but Not Its Deoxynucleotide Triphosphohydrolase Activity, is Regulated by Phosphorylation

Overview

Journal Cell Host Microbe

Publisher Cell Press

Specialties Infectious Diseases
Microbiology

Date 2013 Apr 23

PMID 23601106

Citations 197

Authors

Tommy E White

Alberto Brandariz-Nunez

Jose Carlos Valle-Casuso

Sarah Amie

Laura Anh Nguyen

Baek Kim

Marina Tuzova

Felipe Diaz-Griffero

Affiliations

Soon will be listed here.

Abstract

SAMHD1 is a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and inhibits the ability of retroviruses, notably HIV-1, to infect myeloid cells. Although SAMHD1 is expressed in both cycling and noncycling cells, the antiviral activity of SAMHD1 is limited to noncycling cells. We determined that SAMHD1 is phosphorylated on residue T592 in cycling cells but that this phosphorylation is lost when cells are in a noncycling state. Reverse genetic experiments revealed that SAMHD1 phosphorylated on residue T592 is unable to block retroviral infection, but this modification does not affect the ability of SAMHD1 to decrease cellular dNTP levels. SAMHD1 contains a target motif for cyclin-dependent kinase 1 (cdk1) ((592)TPQK(595)), and cdk1 activity is required for SAMHD1 phosphorylation. Collectively, these findings indicate that phosphorylation modulates the ability of SAMHD1 to block retroviral infection without affecting its ability to decrease cellular dNTP levels.

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References

Arfi V, Riviere L, Jarrosson-Wuilleme L, Goujon C, Rigal D, Darlix J . Characterization of the early steps of infection of primary blood monocytes by human immunodeficiency virus type 1. J Virol. 2008; 82(13):6557-65. PMC: 2447095. DOI: 10.1128/JVI.02321-07. View

Belshan M, Mahnke L, Ratner L . Conserved amino acids of the human immunodeficiency virus type 2 Vpx nuclear localization signal are critical for nuclear targeting of the viral preintegration complex in non-dividing cells. Virology. 2005; 346(1):118-26. DOI: 10.1016/j.virol.2005.10.036. View

Zhang C, de Silva S, Wang J, Wu L . Co-evolution of primate SAMHD1 and lentivirus Vpx leads to the loss of the vpx gene in HIV-1 ancestor. PLoS One. 2012; 7(5):e37477. PMC: 3345027. DOI: 10.1371/journal.pone.0037477. View

White T, Brandariz-Nunez A, Valle-Casuso J, Amie S, Nguyen L, Kim B . Contribution of SAM and HD domains to retroviral restriction mediated by human SAMHD1. Virology. 2012; 436(1):81-90. PMC: 3767443. DOI: 10.1016/j.virol.2012.10.029. View

Kinoshita E, Kinoshita-Kikuta E, Takiyama K, Koike T . Phosphate-binding tag, a new tool to visualize phosphorylated proteins. Mol Cell Proteomics. 2005; 5(4):749-57. DOI: 10.1074/mcp.T500024-MCP200. View

Berger A, Sommer A, Zwarg J, Hamdorf M, Welzel K, Esly N . SAMHD1-deficient CD14+ cells from individuals with Aicardi-Goutières syndrome are highly susceptible to HIV-1 infection. PLoS Pathog. 2011; 7(12):e1002425. PMC: 3234228. DOI: 10.1371/journal.ppat.1002425. View

Fujita M, Otsuka M, Miyoshi M, Khamsri B, Nomaguchi M, Adachi A . Vpx is critical for reverse transcription of the human immunodeficiency virus type 2 genome in macrophages. J Virol. 2008; 82(15):7752-6. PMC: 2493314. DOI: 10.1128/JVI.01003-07. View

Bergamaschi A, Ayinde D, David A, Le Rouzic E, Morel M, Collin G . The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection. J Virol. 2009; 83(10):4854-60. PMC: 2682070. DOI: 10.1128/JVI.00187-09. View

Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Segeral E . SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature. 2011; 474(7353):654-7. PMC: 3595993. DOI: 10.1038/nature10117. View

10.

Ahn J, Hao C, Yan J, DeLucia M, Mehrens J, Wang C . HIV/simian immunodeficiency virus (SIV) accessory virulence factor Vpx loads the host cell restriction factor SAMHD1 onto the E3 ubiquitin ligase complex CRL4DCAF1. J Biol Chem. 2012; 287(15):12550-8. PMC: 3321004. DOI: 10.1074/jbc.M112.340711. View

11.

Lim E, Fregoso O, McCoy C, Matsen F, Malik H, Emerman M . The ability of primate lentiviruses to degrade the monocyte restriction factor SAMHD1 preceded the birth of the viral accessory protein Vpx. Cell Host Microbe. 2012; 11(2):194-204. PMC: 3288607. DOI: 10.1016/j.chom.2012.01.004. View

12.

Sunseri N, OBrien M, Bhardwaj N, Landau N . Human immunodeficiency virus type 1 modified to package Simian immunodeficiency virus Vpx efficiently infects macrophages and dendritic cells. J Virol. 2011; 85(13):6263-74. PMC: 3126535. DOI: 10.1128/JVI.00346-11. View

13.

Errico A, Deshmukh K, Tanaka Y, Pozniakovsky A, Hunt T . Identification of substrates for cyclin dependent kinases. Adv Enzyme Regul. 2010; 50(1):375-99. DOI: 10.1016/j.advenzreg.2009.12.001. View

14.

Goncalves A, Karayel E, Rice G, Bennett K, Crow Y, Superti-Furga G . SAMHD1 is a nucleic-acid binding protein that is mislocalized due to aicardi-goutières syndrome-associated mutations. Hum Mutat. 2012; 33(7):1116-22. DOI: 10.1002/humu.22087. View

15.

Hass R, Gunji H, Datta R, Kharbanda S, Hartmann A, Weichselbaum R . Differentiation and retrodifferentiation of human myeloid leukemia cells is associated with reversible induction of cell cycle-regulatory genes. Cancer Res. 1992; 52(6):1445-50. View

16.

Goujon C, Riviere L, Jarrosson-Wuilleme L, Bernaud J, Rigal D, Darlix J . SIVSM/HIV-2 Vpx proteins promote retroviral escape from a proteasome-dependent restriction pathway present in human dendritic cells. Retrovirology. 2007; 4:2. PMC: 1779362. DOI: 10.1186/1742-4690-4-2. View

17.

Van den Heuvel S, Harlow E . Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993; 262(5142):2050-4. DOI: 10.1126/science.8266103. View

18.

Jin L, Zhou Y, Ratner L . HIV type 2 Vpx interaction with Gag and incorporation into virus-like particles. AIDS Res Hum Retroviruses. 2001; 17(2):105-11. DOI: 10.1089/08892220150217193. View

19.

Traore K, Trush M, George Jr M, Spannhake E, Anderson W, Asseffa A . Signal transduction of phorbol 12-myristate 13-acetate (PMA)-induced growth inhibition of human monocytic leukemia THP-1 cells is reactive oxygen dependent. Leuk Res. 2005; 29(8):863-79. DOI: 10.1016/j.leukres.2004.12.011. View

20.

Hirsch V, Sharkey M, Brown C, Brichacek B, Goldstein S, Wakefield J . Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification. Nat Med. 1998; 4(12):1401-8. PMC: 9513717. DOI: 10.1038/3992. View