Role of SAMHD1 nuclear localization in restriction of HIV-1 and SIVmac

Brandariz-Núñez, Alberto; Valle-Casuso, José Carlos; White, Tommy E.; Laguette, Nadine; Benkirane, Monsef; Brojatsch, Jürgen; Díaz-Griffero, Felipe

doi:10.1186/1742-4690-9-49

Cited by 131 publications

(163 citation statements)

References 41 publications

(72 reference statements)

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“…Similarly, SAMHD1 degradation had been suggested to occur entirely in the nucleus based on the observations that NLS mutants of SAMHD1 (i.e. cytoplasmic) could resist Vpx-mediated degradation (24,26). However, this is in contrast with the fact that Vpx removes both nuclear and cytoplasmic fractions of SAMHD1 during the infection of quiescent lymphocytes.…”

Section: Discussioncontrasting

confidence: 48%

“…This observation is supported by heterokaryon experiments that indicate that SAMHD1 does not possess a nuclear export signal and that therefore once it enters the nucleus, lacks the ability to leave it. Given that Vpx reaches the nucleus, the simplest explanation is that WT Vpx degrades SAMHD1 directly in this location as proposed (24,26). However, the functionality of a Vpx mutant that displays an exquisite cytoplasmic distribution suggests a more complex and perhaps dynamic mechanism of degradation.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the localization of SAMHD1 in the presence or absence of viral challenge is less clear. If most reports indicate SAMHD1 as essentially nuclear (24,26,36,37), a recent study indicated that SAMHD1 could be also found in the cytoplasm, at least in quiescent lymphocytes (38). Similarly, SAMHD1 degradation had been suggested to occur entirely in the nucleus based on the observations that NLS mutants of SAMHD1 (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…A Functional Vpx Mutant Induces the Accumulation of SAMHD1 in the Cell Cytoplasm-Because SAMHD1 is a nuclear protein and WT Vpx displays a composite intracellular distribution, in both nucleus and cytoplasm (20), WT Vpx is likely to interact with SAMHD1 directly in the nucleus, as proposed (24,26). However, we have previously reported that the functional K84A/85A Vpx mutant displays a strict cytoplasmic distribution (20), so that a direct interaction between these two proteins in the nucleus is unlikely.…”

Section: Samhd1 Is Degraded Rapidly and Does Not Leave The Nucleus Dumentioning

confidence: 99%

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Functional Analysis of the Relationship between Vpx and the Restriction Factor SAMHD1

Berger

Turpin

Cordeil

et al. 2012

Journal of Biological Chemistry

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Background: SAMHD1 is a novel antiviral factor counteracted by the viral protein Vpx Results:Several residues in Vpx affect its ability to increase infection and degrade SAMHD1. Conclusion:Vpx functionality correlates with SAMHD1 degradation, but not with Vpx stability and Vpx-Vpx association. Significance:Several mutants provide further insights into the molecular mechanism of Vpx-induced protection.

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Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Samhd1 Is Degraded Rapidly and Does Not Leave The Nucleus Dumentioning

confidence: 99%

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Functional Analysis of the Relationship between Vpx and the Restriction Factor SAMHD1

Berger

Turpin

Cordeil

et al. 2012

Journal of Biological Chemistry

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“…The SAM domain is a putative protein-protein and protein-nucleic acid interaction module, whereas the HD domain is responsible for dNTPase and viral restriction activities (1,(22)(23)(24). Structural and biochemical studies revealed that SAMHD1 was activated by allosteric dGTPinduced tetramerization, which shapes the substrate-binding pocket for dNTP binding and catalysis (25).…”

mentioning

confidence: 99%

Structural basis of cellular dNTP regulation by SAMHD1

Tang

Zhao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

114

200

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The sterile alpha motif and HD domain-containing protein 1 (SAMHD1), a dNTPase, prevents the infection of nondividing cells by retroviruses, including HIV, by depleting the cellular dNTP pool available for viral reverse transcription. SAMHD1 is a major regulator of cellular dNTP levels in mammalian cells. Mutations in SAMHD1 are associated with chronic lymphocytic leukemia (CLL) and the autoimmune condition Aicardi Goutières syndrome (AGS). The dNTPase activity of SAMHD1 can be regulated by dGTP, with which SAMHD1 assembles into catalytically active tetramers. Here we present extensive biochemical and structural data that reveal an exquisite activation mechanism of SAMHD1 via combined action of both GTP and dNTPs. We obtained 26 crystal structures of SAMHD1 in complex with different combinations of GTP and dNTP mixtures, which depict the full spectrum of GTP/dNTP binding at the eight allosteric and four catalytic sites of the SAMHD1 tetramer. Our data demonstrate how SAMHD1 is activated by binding of GTP or dGTP at allosteric site 1 and a dNTP of any type at allosteric site 2. Our enzymatic assays further reveal a robust regulatory mechanism of SAMHD1 activity, which bares resemblance to that of the ribonuclease reductase responsible for cellular dNTP production. These results establish a complete framework for a mechanistic understanding of the important functions of SAMHD1 in the regulation of cellular dNTP levels, as well as in HIV restriction and the pathogenesis of CLL and AGS.HIV restriction factor | dNTP metabolism | tetramerization | triphosphohydrolase | allosteric regulation S AMHD1 is a dNTPase that hydrolyzes dNTPs into deoxyribonucleosides (dNs) and triphosphates (1). It has recently been identified as a restriction factor that blocks infection by a broad range of retroviruses, including HIV-1, in noncycling myeloid-lineage cells and quiescent CD4 + T lymphocytes (2-7). The dNTPase activity of SAMHD1 depletes the cellular dNTP pool, inhibiting the reverse transcription of the viral RNA genome (8-10). SAMHD1 was also found to inhibit infection by certain DNA viruses including herpes simplex virus type 1 (HSV-1) and vaccinia virus in nondividing macrophages (11,12). Apart from viral restriction, SAMHD1 is ubiquitously expressed in both differentiated and undifferentiated cells of various human organs (2, 13), where it functions in the regulation of DNA damage signaling and proper activation of the innate immune response (14, 15). Mutations in SAMHD1, many of which result in deficiency in the dNTPase activity, are associated with chronic lymphocytic leukemia (CLL) (15, 16) and the autoimmune condition AicardiGoutieres syndrome (AGS) (17, 18).It has been recognized that SAMHD1 may play an important role in the regulation of cellular dNTP levels, which are critical to the fidelity of DNA synthesis and the stability of the genome (13). Abnormal size and/or the imbalance of the dNTP pool may activate the S-phase checkpoint for cell cycle arrest (19,20). In mammalian cells, the concentration of cellular dNT...

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A SAMHD1 mutation associated with Aicardi-Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV-1 from its ability to downmodulate type I interferon in humans

et al. 2017

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Mutations in the human SAMHD1 gene are known to correlate with the development of the Aicardi-Goutières Syndrome (AGS), which is an inflammatory encephalopathy that exhibits neurological dysfunction characterized by increased production of type I interferon (IFN); this evidence has lead to the concept that the SAMHD1 protein negatively regulates the type I IFN response. Additionally, the SAMHD1 protein has been shown to prevent efficient HIV-1 infection of macrophages, dendritic cells and resting CD4+ T cells. To gain insights on the SAMHD1 molecular determinants that are responsible for the deregulated production of type I IFN, we explored the biochemical, cellular and antiviral properties of human SAMHD1 mutants known to correlate with the development of Aicardi-Goutières Syndrome. Most of the studied SAMHD1 AGS mutants exhibit defects in the ability to oligomerize, decrease the levels of cellular dNTPs in human cells, localize exclusively to the nucleus, and restrict HIV-1 infection. At least half of the tested variants preserved the ability to be degraded by the lentiviral protein Vpx, and all of them interacted with RNA. Our investigations revealed that the SAMHD1 AGS variant p.G209S preserve all tested biochemical, cellular and antiviral properties, suggesting that this residue is a determinant for the ability of SAMHD1 to negatively regulate the type I interferon response in human patients with AGS. Overall, our work genetically separated the ability of SAMHD1 to negatively regulate the type I IFN response from its ability to restrict HIV-1.

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Role of SAMHD1 nuclear localization in restriction of HIV-1 and SIVmac

Cited by 131 publications

References 41 publications

Functional Analysis of the Relationship between Vpx and the Restriction Factor SAMHD1

Functional Analysis of the Relationship between Vpx and the Restriction Factor SAMHD1

Structural basis of cellular dNTP regulation by SAMHD1

A SAMHD1 mutation associated with Aicardi-Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV-1 from its ability to downmodulate type I interferon in humans

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