HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase
HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase
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DOI：
10.1038/nature10623
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发表时间：
2011-12-15
期刊：
影响因子：
64.8
通讯作者：
Webb, Michelle
中科院分区：
文献类型：
--
作者：
Goldstone, David C.;Ennis-Adeniran, Valerie;Webb, Michelle
SAMHD 1是鼠干扰素（IFN）-γ诱导基因Mg 11的类似物（参考文献1），最近被鉴定为人免疫缺陷病毒-1（HIV-1）限制因子，可阻断树突状细胞和其他髓样细胞中的早期病毒复制（2，3），并且是慢病毒蛋白Vpx的靶点，可缓解HIV-1限制（4-7）。SAMHD 1还与Aicardi-Goutieres综合征（AGS）相关，AGS是一种炎性脑病，其特征为慢性脑脊液淋巴细胞增多和抗病毒细胞因子IFN-α水平升高（8）。与AGS相关的病理学类似于先天性病毒感染，如经胎盘获得性HIV。在这里，我们表明，人SAMHD 1是一个强大的dGTP刺激的三磷酸水解酶，将脱氧核苷三磷酸的组成脱氧核苷和无机三磷酸。SAMHD 1的催化核心的晶体结构揭示了该蛋白质是二聚体的，并且表明了dGTP刺激针对dNTPs的催化活性的分子基础。我们建议，SAMHD 1，这是高度表达的树突状细胞，限制HIV-1复制水解的大部分细胞dNTPs，从而抑制逆转录和病毒互补DNA（cDNA）的合成。
SAMHD1, an analogue of the murine interferon (IFN)-gamma-induced gene Mg11 (ref. 1), has recently been identified as a human immunodeficiency virus-1 (HIV-1) restriction factor that blocks early-stage virus replication in dendritic and other myeloid cells(2,3) and is the target of the lentiviral protein Vpx, which can relieve HIV-1 restriction(4-7). SAMHD1 is also associated with Aicardi-Goutieres syndrome (AGS), an inflammatory encephalopathy characterized by chronic cerebrospinal fluid lymphocytosis and elevated levels of the antiviral cytokine IFN-alpha(8). The pathology associated with AGS resembles congenital viral infection, such as transplacentally acquired HIV. Here we show that human SAMHD1 is a potent dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates to the constituent deoxynucleoside and inorganic triphosphate. The crystal structure of the catalytic core of SAMHD1 reveals that the protein is dimeric and indicates a molecular basis for dGTP stimulation of catalytic activity against dNTPs. We propose that SAMHD1, which is highly expressed in dendritic cells, restricts HIV-1 replication by hydrolysing the majority of cellular dNTPs, thus inhibiting reverse transcription and viral complementary DNA (cDNA) synthesis.