Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit

Kerstin Schott; Nina V. Fuchs; Rita Derua; Bijan Mahboubi; Esther Schnellbächer; Janna Seifried; Christiane Tondera; Heike Schmitz; Caitlin Shepard; Alberto Brandariz-Nuñez; Felipe Diaz-Griffero; Andreas Reuter; Baek Kim; Veerle Janssens; Renate König

doi:10.1038/s41467-018-04671-1

Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit

Kerstin Schott
, Nina V. Fuchs
, Rita Derua
, Bijan Mahboubi
, Esther Schnellbächer
, Janna Seifried
, Christiane Tondera
, Heike Schmitz
, Caitlin Shepard
, Alberto Brandariz-Nuñez
, Felipe Diaz-Griffero
, Andreas Reuter
, Baek Kim
, Veerle Janssens
, Renate König

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

SAMHD1 is a critical restriction factor for HIV-1 in non-cycling cells and its antiviral activity is regulated by T592 phosphorylation. Here, we show that SAMHD1 dephosphorylation at T592 is controlled during the cell cycle, occurring during M/G₁ transition in proliferating cells. Using several complementary proteomics and biochemical approaches, we identify the phosphatase PP2A-B55α responsible for rendering SAMHD1 antivirally active. SAMHD1 is specifically targeted by PP2A-B55α holoenzymes during mitotic exit, in line with observations that PP2A-B55α is a key mitotic exit phosphatase in mammalian cells. Strikingly, as HeLa or activated primary CD4⁺ T cells enter the G₁ phase, pronounced reduction of RT products is observed upon HIV-1 infection dependent on the presence of dephosphorylated SAMHD1. Moreover, PP2A controls SAMHD1 pT592 level in non-cycling monocyte-derived macrophages (MDMs). Thus, the PP2A-B55α holoenzyme is a key regulator to switch on the antiviral activity of SAMHD1.

Original language	English (US)
Article number	2227
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04671-1
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-018-04671-1

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Schott, K., Fuchs, N. V., Derua, R., Mahboubi, B., Schnellbächer, E., Seifried, J., Tondera, C., Schmitz, H., Shepard, C., Brandariz-Nuñez, A., Diaz-Griffero, F., Reuter, A., Kim, B., Janssens, V., & König, R. (2018). Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit. Nature communications, 9(1), Article 2227. https://doi.org/10.1038/s41467-018-04671-1

Schott, K, Fuchs, NV, Derua, R, Mahboubi, B, Schnellbächer, E, Seifried, J, Tondera, C, Schmitz, H, Shepard, C, Brandariz-Nuñez, A, Diaz-Griffero, F, Reuter, A, Kim, B, Janssens, V & König, R 2018, 'Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit', Nature communications, vol. 9, no. 1, 2227. https://doi.org/10.1038/s41467-018-04671-1

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title = "Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit",

abstract = "SAMHD1 is a critical restriction factor for HIV-1 in non-cycling cells and its antiviral activity is regulated by T592 phosphorylation. Here, we show that SAMHD1 dephosphorylation at T592 is controlled during the cell cycle, occurring during M/G1 transition in proliferating cells. Using several complementary proteomics and biochemical approaches, we identify the phosphatase PP2A-B55α responsible for rendering SAMHD1 antivirally active. SAMHD1 is specifically targeted by PP2A-B55α holoenzymes during mitotic exit, in line with observations that PP2A-B55α is a key mitotic exit phosphatase in mammalian cells. Strikingly, as HeLa or activated primary CD4+ T cells enter the G1 phase, pronounced reduction of RT products is observed upon HIV-1 infection dependent on the presence of dephosphorylated SAMHD1. Moreover, PP2A controls SAMHD1 pT592 level in non-cycling monocyte-derived macrophages (MDMs). Thus, the PP2A-B55α holoenzyme is a key regulator to switch on the antiviral activity of SAMHD1.",

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AU - Mahboubi, Bijan

AU - Schnellbächer, Esther

AU - Seifried, Janna

AU - Tondera, Christiane

AU - Schmitz, Heike

AU - Shepard, Caitlin

AU - Brandariz-Nuñez, Alberto

AU - Diaz-Griffero, Felipe

AU - Reuter, Andreas

AU - Kim, Baek

AU - Janssens, Veerle

AU - König, Renate

PY - 2018/12/1

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Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit

Abstract

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