The SAM domain of mouse SAMHD1 is critical for its activation and regulation

Buzovetsky, Olga; Tang, Caroline; Knecht, Kirsten M.; Antonucci, Jenna M.; Wu, Li; Ji, Xiaoyun; Xiong, Yong

doi:10.1038/s41467-017-02783-8

Cited by 18 publications

(15 citation statements)

References 41 publications

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“…Although the SAMHD1 genes can be found among mammals, only primate and mouse SAMHD1 proteins were biochemically and structurally investigated for their dGTP-dependent dNTPase activity ( 14 , 27 ). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, SAMHD1 genes are also found among mammals, including cats, cows, and horses. SAMHD1 proteins of primates ( 14 ) and mice ( 27 , 28 ) were investigated for their roles in lentivirus restriction as well as for their structure and dGTP-dependent dNTPase activity. However, the dNTPase activity of SAMHD1 proteins found in the host species carrying lentiviruses has not been tested.…”

Section: Introductionmentioning

confidence: 99%

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Interplay of ancestral non-primate lentiviruses with the virus-restricting SAMHD1 proteins of their hosts

Mereby

Maehigashi

Holler

et al. 2018

Journal of Biological Chemistry

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Lentiviruses infect both dividing CD4+ T cells and nondividing myeloid cells, and the infected myeloid cells serve as long-living viral reservoirs. Host sterile alpha motif– and histidine-aspartate domain–containing protein 1 (SAMHD1) kinetically restricts reverse transcription of primate lentiviruses, including human immunodeficiency virus, type 1 (HIV-1) and simian immunodeficiency virus (SIV), in nondividing myeloid cells. SAMHD1 enforces this restriction through its dNTP triphosphohydrolase (dNTPase) activity that depletes cellular dNTPs. Some primate lentiviruses, such as HIV-2, SIVsm, and SIVagm, counteract SAMHD1 restriction by using their viral accessory proteins (Vpx or Vpr) that induce the proteosomal degradation of SAMHD1 and increase dNTP levels. SAMHD1 is conserved among non-primate mammals such as cats, cows, and horses that also carry their own lentiviruses (feline and bovine immunodeficiency viruses and equine infectious anemia viruses, respectively). However, whether these viruses also target SAMHD1 is unknown. Here, we tested whether these ancestral non-primate lentiviruses also can counteract their host SAMHD1 proteins by promoting their proteosomal degradation. Using biochemical and various cell-based assays, we observed that SAMHD1 proteins from the non-primate host species display dGTP-dependent dNTPase activity, but that the non-primate lentiviruses fail to proteosomally degrade the SAMHD1 proteins of their hosts. Our findings suggest that accessory protein–mediated proteosomal degradation of SAMHD1 did not exist among the ancestral non-primate lentiviruses and was uniquely gained by some primate lentiviruses after their transmission to primate species.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interplay of ancestral non-primate lentiviruses with the virus-restricting SAMHD1 proteins of their hosts

Mereby

Maehigashi

Holler

et al. 2018

Journal of Biological Chemistry

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“…In humans, the SAM domain is not involved in nuclease activity, and the HD domain is sufficient for dNTP depletion and, therefore, antiviral activity. However, the SAM domain is necessary for allosteric activation and dNTP hydrolysis in mouse SAMHD1 [4,15,47]. The feline SAMHD1 (fSAMHD1) sequence (GenBank Id.…”

Section: Discussionmentioning

confidence: 99%

Interferon γ and α Have Differential Effects on SAMHD1, a Potent Antiviral Protein, in Feline Lymphocytes

Asadian

Bienzle

2019

Viruses

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Sterile alpha motif and histidine/aspartic domain-containing protein 1 (SAMHD1) is a protein with anti-viral, anti-neoplastic, and anti-inflammatory properties. By degrading cellular dNTPs to constituent deoxynucleoside and free triphosphate, SAMHD1 limits viral DNA synthesis and prevents replication of HIV-1 and some DNA viruses such as HBV, vaccinia, and HSV-1. Recent findings suggest SAMHD1 is broadly active against retroviruses in addition to HIV-1, such as HIV-2, FIV, BIV, and EIAV. Interferons are cytokines produced by lymphocytes and other cells that induce a wide array of antiviral proteins, including some with activity again lentiviruses. Here we evaluated the role of IFNs on SAMHD1 gene expression, transcription, and post-translational modification in a feline CD4+ T cell line (FeTJ) and in primary feline CD4+ T lymphocytes. SAMHD1 mRNA in FetJ cells increased in a dose-related manner in response to IFNγ treatment concurrent with increased nuclear localization and phosphorylation. IFNα treatment induced SAMHD1 mRNA but did not significantly alter SAMHD1 protein detection, phosphorylation, or nuclear translocation. In purified primary feline CD4+ lymphocytes, IL2 supplementation increased SAMHD1 expression, but the addition of IFNγ did not further alter SAMHD1 protein expression or nuclear localization. Thus, the effect of IFNγ on SAMHD1 expression is cell-type dependent, with increased translocation to the nucleus and phosphorylation in FeTJ but not primary CD4+ lymphocytes. These findings imply that while SAMH1 is inducible by IFNγ, overall activity is cell type and compartment specific, which is likely relevant to the establishment of lentiviral reservoirs in quiescent lymphocyte populations.

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“…Only isoform 1 of mSAMHD1 contains a phosphorylation site at residue T634 capable of regulating its antiviral activity while isoform 2 has no comparable site [12,240]. While apo-and holo-hSAMHD1 exists predominantly as a monomer or tetramer, respectively, apo-and holo-mSAMHD1 exists primarily as a dimer and slowly forms tetramers in the presence of non-hydrolyzable nucleotides [241]. This slow progression into a tetramer suggests mSAMHD1 is regulated differently than hSAMHD1 and has a more complex assembly formation.…”

Section: Comparisons Between Ags Animal Modelsmentioning

confidence: 99%

SAMHD1 Functions and Human Diseases

Coggins

Mahboubi

Schinazi

et al. 2020

Viruses

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Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells and a variety of viral pathogens. While the process of dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) and thymidine kinase (TK), has been extensively investigated, a negative regulatory mechanism of dNTP pools was recently found to involve sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, dNTP triphosphohydrolase activity of SAMHD1 degrades dNTPs into their 2′-deoxynucleoside (dN) and triphosphate subparts, steadily depleting intercellular dNTP pools. The differential expression levels and activation states of SAMHD1 in various cell types contributes to unique dNTP pools that either aid (i.e., dividing T cells) or restrict (i.e., nondividing macrophages) viral replication that consumes cellular dNTPs. Genetic mutations in SAMHD1 induce a rare inflammatory encephalopathy called Aicardi–Goutières syndrome (AGS), which phenotypically resembles viral infection. Recent publications have identified diverse roles for SAMHD1 in double-stranded break repair, genome stability, and the replication stress response through interferon signaling. Finally, a series of SAMHD1 mutations were also reported in various cancer cell types while why SAMHD1 is mutated in these cancer cells remains to investigated. Here, we reviewed a series of studies that have begun illuminating the highly diverse roles of SAMHD1 in virology, immunology, and cancer biology.

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The SAM domain of mouse SAMHD1 is critical for its activation and regulation

Cited by 18 publications

References 41 publications

Interplay of ancestral non-primate lentiviruses with the virus-restricting SAMHD1 proteins of their hosts

Interplay of ancestral non-primate lentiviruses with the virus-restricting SAMHD1 proteins of their hosts

Interferon γ and α Have Differential Effects on SAMHD1, a Potent Antiviral Protein, in Feline Lymphocytes

SAMHD1 Functions and Human Diseases

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