期刊
NATURE MEDICINE
卷 20, 期 8, 页码 936-941出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3626
关键词
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资金
- US National Institutes of Health [R01 A1087390, R21 AI102824, GM104198, AI049781]
- Korean Institute for Basic Science [EM1402]
- Korean Basic Science Research Program [2011-0014523]
- Korean Creative Research Initiative Program (Research Center for Antigen Presentation) [2006-0050689]
- National Research Foundation - Ministry of Education, Science, and Technology of Korea
- Ministry of Science, ICT & Future Planning, Republic of Korea [IBS-R008-D1-2014-A00] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2006-0050689, 2011-0014523] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1)(1,2) is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool(3-5). However, phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels(6-8), which is not consistent with a role for SAMHD1 dNTPase activity in HIV-1 restriction. Here, we show that SAMHD1 possesses RNase activity and that the RNase but not the dNTPase function is essential for HIV-1 restriction. By enzymatically characterizing Aicardi-Goutieres syndrome (AGS)-associated SAMHD1 mutations and mutations in the allosteric dGTP-binding site of SAMHD1 for defects in RNase or dNTPase activity, we identify SAMHD1 point mutants that cause loss of one or both functions. The RNase-positive and dNTPase-negative SAMHD1(D137N) mutant is able to restrict HIV-1 infection, whereas the RNase-negative and dNTPase-positive SAMHD1(Q548A) mutant is defective for HIV-1 restriction. SAMHD1 associates with HIV-1 RNA and degrades it during the early phases of cell infection. SAMHD1 silencing in macrophages and CD4(+) T cells from healthy donors increases HIV-1 RNA stability, rendering the cells permissive for HIV-1 infection. Furthermore, phosphorylation of SAMHD1 at T592 negatively regulates its RNase activity in cells and impedes HIV-1 restriction. Our results reveal that the RNase activity of SAMHD1 is responsible for preventing HIV-1. infection by directly degrading the HIV-1 RNA.
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