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

White, Tommy E.; Brandariz-Núñez, Alberto; Martínez‐López, Alicia; Knowlton, Caitlin; Lenzi, Gina M.; Kim, Baek; Ivanov, Dmitri N.; Díaz-Griffero, Felipe

doi:10.1002/humu.23201

Cited by 28 publications

(33 citation statements)

References 64 publications

(168 reference statements)

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“…Mutations in the SAMHD1 gene may alter enzyme synthesis and result in uncontrolled inflammatory responses, mainly mediated through the increased production of type I IFN (Rice et al, 2009). Mutations in the SAMHD1 gene are associated with an autoimmune disorder through the irregular response of type I IFN, which characterizes Aicardi-Goutières syndrome, in which there is marked production of IL-12 and TNF-α (White et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

The SAMHD1 rs6029941 (A/G) Polymorphism Seems to Influence the HTLV-1 Proviral Load and IFN-Alpha Levels

Queiroz

Amoras

Moura

et al. 2020

Front. Cell. Infect. Microbiol.

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SAMHD1, a host dNTPase, acts as a retroviral restriction factor by degrading the pool of nucleotides available for the initial reverse transcription of retroviruses, including HTLV-1. Polymorphisms in the SAMDH1 gene may alter the enzymatic expression and influence the course of infection by the virus. The present study investigated the effect of polymorphisms on HTLV-1 infection susceptibility and on progression to disease in 108 individuals infected by HTLV-1 (47 symptomatic and 61 asymptomatic) and 100 individuals in a control group. SAMHD1 rs6029941 (G/A) genotyping and HTLV-1 proviral load measurements were performed using real-time PCR and plasma IFN-α was measured by ELISA. Polymorphism frequency was not associated with HTLV-1 infection susceptibility or with the presence of symptoms. The proviral load was significantly higher in symptomatic individuals with the G allele (p = 0.0143), which presented lower levels of IFN-α (p = 0.0383). SAMHD1 polymorphism is associated with increased proviral load and reduced levels of IFN-α in symptomatic patients, and may be a factor that contributes to the appearance of disease symptoms.

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Section: Discussionmentioning

confidence: 99%

The SAMHD1 rs6029941 (A/G) Polymorphism Seems to Influence the HTLV-1 Proviral Load and IFN-Alpha Levels

Queiroz

Amoras

Moura

et al. 2020

Front. Cell. Infect. Microbiol.

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“…ISD-PS (biotin tagged ISD-PS), poly (dA:dT) [biotin tagged poly (dA:dT)] and poly (dG:dC) [biotin tagged poly (dG:dC)] were all synthesized by Sangon Biotech (China) and their sequences were presented in Table 1. ISD-PS is an RNA analog carrying a biotin tag (34). Poly I:C was purchased from Sigma (USA).…”

Section: Methodsmentioning

confidence: 99%

The Fish-Specific Protein Kinase (PKZ) Initiates Innate Immune Responses via IRF3- and ISGF3-Like Mediated Pathways

et al. 2019

Front. Immunol.

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PKZ is a fish-specific protein kinase containing Zα domains. PKZ is known to induce apoptosis through phosphorylating eukaryotic initiation factor 2α kinase (eIF2α) in the same way as double-stranded RNA-dependent protein kinase (PKR), but its exact role in detecting pathogens remains to be fully elucidated. Herein, we have found that PKZ acts as a fish-specific DNA sensor by initiating IFN expression through IRF3- or ISGF3-like mediated pathways. The expression pattern of PKZ is similar to those of innate immunity mediators stimulated by poly (dA:dT) and poly (dG:dC). DNA-PKZ interaction can enhance PKZ phosphorylation and dimerization in vitro . These findings indicate that PKZ participates in cytoplasmic DNA-mediated signaling. Subcellular localization assays have also shown that PKZ is located in the cytoplasm, which suggests that PKZ acts as a cytoplasmic PRR. Meanwhile, co-IP assays have shown that PKZ can separately interact with IRF3, STING, ZDHHC1, eIF2α, IRF9, and STAT2. Further investigations have revealed that PKZ can activate IRF3 and STAT2; and that IRF3-dependent and ISGF3-like dependent mediators are critical for PKZ-induced IFN expression. These results demonstrate that PKZ acts as a special DNA pattern-recognition receptor, and that PKZ can trigger immune responses through IRF3-mediated or ISGF3-like mediated pathways in fish.

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“…AGS-associated mutations are found throughout the SAMHD1 gene and often lead to defects in the enzyme's ability to oligomerize and reduce dNTP levels. All SAMHD1 mutants identified in AGS patients lost their ability to block HIV-1 infection except for G209S [196]. The G209S SAMHD1 mutant represents a unique variant, which differentiates the ability of SAMHD1 to restrict HIV-1 and regulate type 1 IFN responses.…”

Section: Samhd1 Plays a Role In The Innate Immune Response And Is Mutmentioning

confidence: 96%

SAMHD1 Functions and Human Diseases

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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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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

Cited by 28 publications

References 64 publications

The SAMHD1 rs6029941 (A/G) Polymorphism Seems to Influence the HTLV-1 Proviral Load and IFN-Alpha Levels

The SAMHD1 rs6029941 (A/G) Polymorphism Seems to Influence the HTLV-1 Proviral Load and IFN-Alpha Levels

The Fish-Specific Protein Kinase (PKZ) Initiates Innate Immune Responses via IRF3- and ISGF3-Like Mediated Pathways

SAMHD1 Functions and Human Diseases

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