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The ribonuclease activity of SAMHD1 is required for HIV-1 restriction Highly Cited Paper

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Title
The ribonuclease activity of SAMHD1 is required for HIV-1 restriction
Author(s)
Jeongmin Ryoo; Jongsu Choi; Changhoon Oh; Sungchul Kim; Minji Seo; Seok-Young Kim; Daekwan Seo; Jongkyu Kim; Tommy E. White; Alberto Brandariz-Nunez; Felipe Diaz-Griffero; Cheol-Heui Yun; Joseph A Hollenbaugh; Baek Kim; Daehyun Baek; Kwangseog Ahn
Publication Date
2014-08
Journal
NATURE MEDICINE, v.20, no.8, pp.936 - 941
Publisher
NATURE PUBLISHING GROUP
Abstract
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 pool3–5. However, phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels6–8, 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-Goutières 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 SAMHD1D137N mutant is able to restrict HIV-1 infection, whereas the RNase-negative and dNTPase-positive SAMHD1Q548A 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.
URI
https://pr.ibs.re.kr/handle/8788114/949
ISSN
1078-8956
Appears in Collections:
Center for RNA Research(RNA 연구단) > Journal Papers (저널논문)
Files in This Item:
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