Dataset Information

Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55? 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-B55? responsible for rendering SAMHD1 antivirally active. SAMHD1 is specifically targeted by PP2A-B55? holoenzymes during mitotic exit, in line with observations that PP2A-B55? 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-B55? holoenzyme is a key regulator to switch on the antiviral activity of SAMHD1.

SUBMITTER: Schott K

PROVIDER: S-EPMC5993806 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Schott Kerstin K Fuchs Nina V NV Derua Rita R Mahboubi Bijan B Schnellbächer Esther E Seifried Janna J Tondera Christiane C Schmitz Heike H Shepard Caitlin C Brandariz-Nuñez Alberto A Diaz-Griffero Felipe F Reuter Andreas A Kim Baek B Janssens Veerle V König Renate R

Nature communications 20180608 1

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/G<sub>1</sub> 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 holo ...[more]

PMID: 29884836

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Project description:BackgroundClass IIa histone deacetylase (HDAC) isoforms such as HDAC5 are critical signal-responsive repressors of maladaptive cardiomyocyte hypertrophy, through nuclear interactions with transcription factors including myocyte enhancer factor-2. ?-Adrenoceptor (?-AR) stimulation, a signal of fundamental importance in regulating cardiac function, has been proposed to induce both phosphorylation-independent nuclear export and phosphorylation-dependent nuclear accumulation of cardiomyocyte HDAC5. The relative importance of phosphorylation at Ser259/Ser498 versus Ser279 in HDAC5 regulation is also controversial. We aimed to determine the impact of ?-AR stimulation on the phosphorylation, localization, and function of cardiomyocyte HDAC5 and delineate underlying molecular mechanisms.Methods and resultsA novel 3-dimensional confocal microscopy method that objectively quantifies the whole-cell nuclear/cytoplasmic distribution of green fluorescent protein tagged HDAC5 revealed the ?-AR agonist isoproterenol to induce ?1-AR-mediated and protein kinase A-dependent HDAC5 nuclear accumulation in adult rat cardiomyocytes, which was accompanied by dephosphorylation at Ser259/279/498. Mutation of Ser259/Ser498 to Ala promoted HDAC5 nuclear accumulation and myocyte enhancer factor-2 inhibition, whereas Ser279 ablation had no such effect and did not block isoproterenol-induced nuclear accumulation. Inhibition of the Ser/Thr phosphatase PP2A blocked isoproterenol-induced HDAC5 dephosphorylation. Co-immunoprecipitation revealed a specific interaction of HDAC5 with the PP2A targeting subunit B55?, as well as catalytic and scaffolding subunits, which increased >3-fold with isoproterenol. Knockdown of B55? in neonatal cardiomyocytes attenuated isoproterenol-induced HDAC5 dephosphorylation.Conclusions?-AR stimulation induces HDAC5 nuclear accumulation in cardiomyocytes by a mechanism that is protein kinase A-dependent but requires B55?-PP2A-mediated dephosphorylation of Ser259/Ser498 rather than protein kinase A-mediated phosphorylation of Ser279.

Dataset Information

Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55? holoenzymes during mitotic exit.

Publications

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

Similar Datasets

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