Role of SAMHD1 nuclear localization in restriction of HIV-1 and SIVmac

Retrovirology

Felipe Diaz-Griffero¹  Jurgen Brojatsch¹  Monsef Benkirane²  Nadine Laguette²  Tommy E White¹  Jose Carlos Valle-Casuso¹  Alberto Brandariz-Nuñez¹ 

[1] Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, Bronx, NY, 10461, USA;Laboratoire de Virologie Moléculaire, Institut de Génétique Humaine, CNRS-UPR 1142, 141 rue de la Cardonille, 34296, Montpellier, cedex 5, France

关键词: Degradation;    SIV;    HIV-1;    Vpx;    Nuclear localization;    Restriction;    SAMHD;   

Others  :  1209294
DOI  :  10.1186/1742-4690-9-49

 received in 2012-02-14, accepted in 2012-06-12,  发布年份 2012

【 摘 要 】

Background

SAMHD1 is a nuclear protein that blocks lentiviral infection before reverse transcription in macrophages and dendritic cells. The viral accessory protein Vpx overcomes the SAMHD1-mediated lentiviral block by inducing its proteasomal degradation.

Results

Here, we identified the nuclear localization signal (NLS) of SAMHD1, and studied its contribution to restriction of HIV-1 and SIVmac. By studying the cellular distribution of different SAMHD1 variants, we mapped the nuclear localization of SAMHD1 to residues ¹¹KRPR¹⁴. Mutagenesis of these residues changed the cellular distribution of SAMHD1 from the nucleus to the cytoplasm. SAMHD1 mutants that lost nuclear localization restricted HIV-1 and SIV as potently as the wild type protein. Interestingly, SAMHD1 mutants that localized to the cytoplasm were not degraded by nuclear Vpx alleles. Therefore, nuclear Vpx alleles require nuclear localization of SAMHD1 in order to induce its degradation. In agreement, SIVmac viruses encoding Vpx did not overcome the restriction imposed by the cytoplasmic variants of SAMHD1.

Conclusions

We mapped the NLS of SAMHD1 to residues ¹¹KRPR¹⁴ and studied the contribution of SAMHD1 nuclear localization to restriction of HIV-1 and SIV. These experiments demonstrate that cytoplasmic variants of SAMHD1 potently block lentiviral infection and are resistant to Vpx-mediated degradation. The nuclear Vpx alleles studied here are only capable of degrading a nuclearly localized SAMHD1 suggesting that Vpx-mediated degradation of SAMHD1 is initiated in the nucleus.

【 授权许可】

   
2012 Brandariz-Nunes et al.; licensee BioMed Central Ltd.

【 图 表 】

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