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

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Article number2227
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Holoenzymes
human immunodeficiency virus
Phosphoric Monoester Hydrolases
Antiviral Agents
HIV-1
constrictions
Cells
Phosphorylation
phosphatases
T-cells
Macrophages
Switches
G1 Phase
monocytes
Proteomics
phosphorylation
HIV Infections
macrophages
regulators
Cell Cycle

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Schott, K., Fuchs, N. V., Derua, R., Mahboubi, B., Schnellbächer, E., Seifried, J., ... König, R. (2018). Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit. Nature Communications, 9(1), [2227]. https://doi.org/10.1038/s41467-018-04671-1

Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit. / Schott, Kerstin; Fuchs, Nina V.; Derua, Rita; Mahboubi, Bijan; Schnellbächer, Esther; Seifried, Janna; Tondera, Christiane; Schmitz, Heike; Shepard, Caitlin; Brandariz-Nuñez, Alberto; Diaz-Griffero, Felipe; Reuter, Andreas; Kim, Baek; Janssens, Veerle; König, Renate.

In: Nature Communications, Vol. 9, No. 1, 2227, 01.12.2018.

Research output: Contribution to journalArticle

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
Schott, Kerstin ; Fuchs, Nina V. ; Derua, Rita ; Mahboubi, Bijan ; Schnellbächer, Esther ; Seifried, Janna ; Tondera, Christiane ; Schmitz, Heike ; Shepard, Caitlin ; Brandariz-Nuñez, Alberto ; Diaz-Griffero, Felipe ; Reuter, Andreas ; Kim, Baek ; Janssens, Veerle ; König, Renate. / Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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