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

Jeongmin Ryoo, Jongsu Choi, Changhoon Oh, Sungchul Kim, Minji Seo, Seok Young Kim, Daekwan Seo, Jongkyu Kim, Tommy E. White, Alberto Brandariz-Nuñez, Felipe Diaz-Griffero, Cheol Heui Yun, Joseph A. Hollenbaugh, Baek Kim, Daehyun Baek, Kwangseog Ahn

Research output: Contribution to journalArticle

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Abstract

The HIV-1 restriction factor SAM domain-and HD domain-containing protein 1 (SAMHD1) is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool. However, phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels, 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 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.

Original languageEnglish (US)
Pages (from-to)936-941
Number of pages6
JournalNature Medicine
Volume20
Issue number8
DOIs
StatePublished - 2014

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Ribonucleases
HIV-1
Proteins
HIV Infections
Phosphorylation
RNA
Sterile Alpha Motif
Protein Domains
Aicardi Syndrome
Mutation
T-cells
Macrophages
RNA Stability
Binding Sites

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Ryoo, J., Choi, J., Oh, C., Kim, S., Seo, M., Kim, S. Y., ... Ahn, K. (2014). The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nature Medicine, 20(8), 936-941. https://doi.org/10.1038/nm.3626

The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. / Ryoo, Jeongmin; Choi, Jongsu; Oh, Changhoon; Kim, Sungchul; Seo, Minji; Kim, Seok Young; Seo, Daekwan; Kim, Jongkyu; White, Tommy E.; Brandariz-Nuñez, Alberto; Diaz-Griffero, Felipe; Yun, Cheol Heui; Hollenbaugh, Joseph A.; Kim, Baek; Baek, Daehyun; Ahn, Kwangseog.

In: Nature Medicine, Vol. 20, No. 8, 2014, p. 936-941.

Research output: Contribution to journalArticle

Ryoo, J, Choi, J, Oh, C, Kim, S, Seo, M, Kim, SY, Seo, D, Kim, J, White, TE, Brandariz-Nuñez, A, Diaz-Griffero, F, Yun, CH, Hollenbaugh, JA, Kim, B, Baek, D & Ahn, K 2014, 'The ribonuclease activity of SAMHD1 is required for HIV-1 restriction', Nature Medicine, vol. 20, no. 8, pp. 936-941. https://doi.org/10.1038/nm.3626
Ryoo, Jeongmin ; Choi, Jongsu ; Oh, Changhoon ; Kim, Sungchul ; Seo, Minji ; Kim, Seok Young ; Seo, Daekwan ; Kim, Jongkyu ; White, Tommy E. ; Brandariz-Nuñez, Alberto ; Diaz-Griffero, Felipe ; Yun, Cheol Heui ; Hollenbaugh, Joseph A. ; Kim, Baek ; Baek, Daehyun ; Ahn, Kwangseog. / The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. In: Nature Medicine. 2014 ; Vol. 20, No. 8. pp. 936-941.
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