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SAMHD1

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https://www.readbyqxmd.com/read/28444859/roles-of-samhd1-in-antiviral-defense-autoimmunity-and-cancer
#1
REVIEW
Miaomiao Li, Dong Zhang, Mengying Zhu, Yuxian Shen, Wei Wei, Songcheng Ying, Heinrich Korner, Jun Li
The enzyme, sterile α motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) diminishes infection of human immunodeficiency virus type 1 (HIV-1) by hydrolyzing intracellular deoxynucleotide triphosphates (dNTPs) in myeloid cells and resting CD4+ T cells. This dNTP degradation reduces the dNTP concentration to a level insufficient for viral cDNA synthesis, thereby inhibiting retroviral replication. This antiviral enzymatic activity can be inhibited by viral protein X (Vpx). The HIV-2/SIV Vpx causes degradation of SAMHD1, thus interfering with the SAMHD1-mediated restriction of retroviral replication...
April 25, 2017: Reviews in Medical Virology
https://www.readbyqxmd.com/read/28436707/samhd1-protects-cancer-cells-from-various-nucleoside-based-antimetabolites
#2
Nikolas Herold, Sean G Rudd, Kumar Sanjiv, Juliane Kutzner, Julia Bladh, Cynthia B J Paulin, Thomas Helleday, J I Henter, Torsten Schaller
Recently, we demonstrated that sterile alpha motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemic (AML) cells to the cytotoxicity of cytarabine (ara-C), the most important drug in AML treatment. Ara-C is intracellularly converted by the canonical dNTP synthesis pathway to ara-CTP, which serves as a substrate but not an allosteric activator of SAMHD1. Using an AML mouse model, we show here that wild type but not catalytically inactive SAMHD1 reduces ara-C treatment efficacy in vivo...
April 24, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28401188/samhd1-is-a-barrier-to-antimetabolite-based-cancer-therapies
#3
Sean G Rudd, Torsten Schaller, Nikolas Herold
The outcome of acute myelogenous leukemia (AML) therapy depends on the propensity of leukemic blasts to accumulate ara-CTP, the active triphosphate of cytarabine (ara-C). We identified sterile α motif and HD domain-containing protein 1 (SAMHD1) as an ara-CTPase that protects cancer cells from cytarabine-induced toxicity. Therefore, we propose targeting SAMHD1 as a strategy to potentiate cytarabine and possibly other antimetabolite-based therapies.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28398823/the-samhd1-dntp-triphosphohydrolase-is-controlled-by-a-redox-switch
#4
Christopher H Mauney, LeAnn C Rogers, Reuben S Harris, Larry W Daniel, Nelmi O Devarie-Baez, Hanzhi Wu, Cristina M Furdui, Leslie B Poole, Fred W Perrino, Thomas Hollis
AIMS: Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. RESULTS: Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools...
April 18, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28389709/-familial-chilblain-lupus-type-1-interferonopathy-with-model-character
#5
REVIEW
C Fiehn
Familial chilblain lupus belongs to the group of type 1 interferonopathies and is particularly characterized by typical skin manifestations and ischemia of the acra. There are various mutations that can lead to this autosomal dominant disease. A mutation in the TREX-1 gene has been most frequently found; however, families with mutations in the SAMHD1 gene and recently in the gene which codes for the stimulator of interferon genes (STING) protein were also described. A common feature of these genetic defects is that they are all involved in the process of detection of intracellular free DNA, which as a result leads to increased production of type 1 interferons and the induced gene products...
April 7, 2017: Zeitschrift Für Rheumatologie
https://www.readbyqxmd.com/read/28387595/interferon-stimulated-gene-expression-as-a-preferred-biomarker-for-disease-activity-in-aicardi-gouti%C3%A3-res-syndrome
#6
Ben X Wang, Stephanie A Grover, Peter Kannu, Grace Yoon, Ronald M Laxer, E Ann Yeh, Eleanor N Fish
Aicardi-Goutières syndrome (AGS) is an early-onset, genetic disease characterized by recurrent fever, multifocal lesions of the brain, and systemic autoimmunity. We report on 3 AGS patients, 2 siblings with an RNASEH2A gene mutation and 1 patient with a SAMHD1 gene mutation. Serial analysis of peripheral blood from all 3 AGS patients showed consistently elevated expression of the interferon-stimulated genes (ISGs): ISG15, RSAD2, and IFI27, not observed in unaffected family members. Enumeration of circulating white blood cells and platelets and examination of C-reactive protein showed no significant deviation from the normal range for Patient 2 with the RNASEH2A mutation and Patient 3 with the SAMHD1 mutation, even when Patient 2 had magnetic resonance imaging abnormalities and ongoing febrile episodes...
April 2017: Journal of Interferon & Cytokine Research
https://www.readbyqxmd.com/read/28359840/samhd1-is-active-in-cycling-cells-permissive-to-hiv-1-infection
#7
Roger Badia, Maria Pujantell, Javier Torres-Torronteras, Luis Menéndez-Arias, Ramón Martí, Albert Ruzo, Eduardo Pauls, Bonaventura Clotet, Ester Ballana, José A Esté, Eva Riveira-Muñoz
SAMHD1 is a triphosphohydrolase that restricts HIV-1 by limiting the intracellular dNTP pool required for reverse transcription. Although SAMHD1 is expressed and active/unphosphorylated in most cell lines, its restriction activity is thought to be relevant only in non-cycling cells. However, an in depth evaluation of SAMHD1 function and relevance in cycling cells is required. Here, we show that SAMHD1-induced degradation by HIV-2 Vpx affects the dNTP pool and HIV-1 replication capacity in the presence of the 3'-azido-3'-deoxythymidine (AZT) in cycling cells...
June 2017: Antiviral Research
https://www.readbyqxmd.com/read/28321930/uncovering-allostery-and-regulation-in-samhd1-through-molecular-dynamics-simulations
#8
Kajwal Kumar Patra, Akash Bhattacharya, Swati Bhattacharya
The human sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a retroviral restriction factor in myeloid cells and non-cycling CD4+ T cells, a feature imputed to its phosphohydrolase activity-the enzyme depletes the cellular dNTP levels inhibiting reverse transcription. The functionally active form of SAMHD1 is an allosterically triggered tetramer which utilizes GTP-Mg(+2) -dNTP cross bridges to link and stabilize adjacent monomers. However, very little is known about how it assembles into a tetramer and how long the tetramer stays intact...
March 21, 2017: Proteins
https://www.readbyqxmd.com/read/28289923/tocilizumab-reverses-cerebral-vasculopathy-in-a-patient-with-homozygous-samhd1-mutation
#9
REVIEW
Michael Henrickson, Heng Wang
An auto-inflammatory syndrome consequent to SAMHD1 mutations involves cerebral vasculopathy characterized by multifocal stenosis and aneurysms within large arteries, moyamoya, chronic ischemia, and early-onset strokes (SAMS). While this condition involves the innate immune system, additional clinical features mimic systemic lupus erythematosus. Mutations in this gene can also cause a subset of the rare genetic condition Aicardi-Goutières syndrome. To date, no established therapy successfully prevents disease progression...
March 13, 2017: Clinical Rheumatology
https://www.readbyqxmd.com/read/28284276/zinc-binding-site-of-human-immunodeficiency-virus-2-vpx-prevents-instability-and-dysfunction-of-the-protein
#10
Minami Yamamoto, Ryoko Koga, Haruna Fujino, Kazunori Shimagaki, Halil Ibrahim Ciftci, Masahiro Kamo, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita
Human immunodeficiency virus 2 Vpx coordinates zinc through residues H39, H82, C87 and C89. We reported previously that H39, H82 and C87 mutants maintain Vpx activity to facilitate the degradation of SAMHD1. Herein, the expression of Vpx mutants in cells was examined in detail. We demonstrated that the zinc-binding site stabilizes the protein to keep its function in virus growth when low levels of Vpx are expressed. At higher levels of expression, Vpx aggregation could occur, and zinc binding would suppress such aggregation...
February 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28251415/a-molecular-dynamics-simulation-study-decodes-the-early-stage-of-the-disassembly-process-abolishing-the-human-samhd1-function
#11
Francesca Cardamone, Federico Iacovelli, Giovanni Chillemi, Mattia Falconi, Alessandro Desideri
The human sterile alpha motif SAM and HD domain-containing protein 1 (SAMHD1) restricts in non-cycling cells type the infection of a large range of retroviruses including HIV-1, reducing the intracellular pool concentration of deoxynucleoside triphosphates (dNTPs) required for the reverse transcription of the viral genome. The enzyme is in equilibrium between different forms depending on bound cofactors and substrate. In this work, two SAMHD1 three-dimensional models have been investigated through classical molecular dynamics simulation, to define the role of cofactors and metal ions in the association of the tetrameric active form...
March 1, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28250118/imaging-hiv-1-genomic-dna-from-entry-through-productive-infection
#12
Ryan D Stultz, Jennifer J Cenker, David McDonald
In order to track the fate of HIV-1 particles from early entry events through productive infection, we developed a method to visualize HIV-1 DNA reverse transcription complexes by incorporation and fluorescent labeling of the thymidine analog 5-ethynyl-2' -deoxyuridine (EdU) into nascent viral DNA during cellular entry. Monocyte-derived macrophages were chosen as natural targets of HIV-1 which do not divide and therefore do not incorporate the EdU into chromosomal DNA, which would obscure detection of intranuclear HIV-1 genomes...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28229507/a-samhd1-mutation-associated-with-aicardi-gouti%C3%A3-res-syndrome-uncouples-the-ability-of-samhd1-to-restrict-hiv-1-from-its-ability-to-downmodulate-type-i-interferon-in-humans
#13
Tommy E White, Alberto Brandariz-Nuñez, Alicia Martinez-Lopez, Caitlin Knowlton, Gina Lenzi, Baek Kim, Dmitri Ivanov, Felipe Diaz-Griffero
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...
February 22, 2017: Human Mutation
https://www.readbyqxmd.com/read/28228523/vpx-overcomes-a-samhd1-independent-block-to-hiv-reverse-transcription-that-is-specific-to-resting-cd4-t-cells
#14
Hanna-Mari Baldauf, Lena Stegmann, Sarah-Marie Schwarz, Ina Ambiel, Maud Trotard, Margarethe Martin, Manja Burggraf, Gina M Lenzi, Helena Lejk, Xiaoyu Pan, Oliver I Fregoso, Efrem S Lim, Libin Abraham, Laura A Nguyen, Frank Rutsch, Renate König, Baek Kim, Michael Emerman, Oliver T Fackler, Oliver T Keppler
Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) of the incoming viral RNA genome. In this context, dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28220857/samhd1-enhances-nucleoside-analogue-efficacy-against-hiv-1-in-myeloid-cells
#15
Paula Ordonez, Simone Kunzelmann, Harriet C T Groom, Melvyn W Yap, Simon Weising, Chris Meier, Kate N Bishop, Ian A Taylor, Jonathan P Stoye
SAMHD1 is an intracellular enzyme that specifically degrades deoxynucleoside triphosphates into component nucleoside and inorganic triphosphate. In myeloid-derived dendritic cells and macrophages as well as resting T-cells, SAMHD1 blocks HIV-1 infection through this dNTP triphosphohydrolase activity by reducing the cellular dNTP pool to a level that cannot support productive reverse transcription. We now show that, in addition to this direct effect on virus replication, manipulating cellular SAMHD1 activity can significantly enhance or decrease the anti-HIV-1 efficacy of nucleotide analogue reverse transcription inhibitors presumably as a result of modulating dNTP pools that compete for recruitment by viral polymerases...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28203649/increased-iron-export-by-ferroportin-induces-restriction-of-hiv-1-infection-in-sickle-cell-disease
#16
Namita Kumari, Tatiana Ammosova, Sharmin Diaz, Xionghao Lin, Xiaomei Niu, Andrey Ivanov, Marina Jerebtsova, Subhash Dhawan, Patricia Oneal, Sergei Nekhai
The low incidence of HIV-1 infection in patients with sickle cell disease (SCD) and inhibition of HIV-1 replication in vitro under the conditions of low intracellular iron or heme treatment suggests a potential restriction of HIV-1 infection in SCD. We investigated HIV-1 ex vivo infection of SCD peripheral blood mononuclear cells (PBMCs) and found that HIV-1 replication was inhibited at the level of reverse transcription (RT) and transcription. We observed increased expression of heme and iron-regulated genes, previously shown to inhibit HIV-1, including ferroportin, IKBα, HO-1, p21, and SAM domain and HD domain-containing protein 1 (SAMHD1)...
December 27, 2016: Blood Advances
https://www.readbyqxmd.com/read/28202763/inhibition-of-vpx-mediated-samhd1-and-vpr-mediated-hltf-degradation-by-selective-disruption-of-viral-crl4-dcaf1-e3-ubiquitin-ligase-assembly
#17
Hong Wang, Haoran Guo, Jiaming Su, Yajuan Rui, Wenwen Zheng, Wenying Gao, Wenyan Zhang, Zhaolong Li, Guanchen Liu, Wei Wei, Xiao-Fang Yu
The lentiviral accessory proteins Vpx and Vpr are known to utilize CRL4 (DCAF1) E3 ligase to induce the degradation of the host restriction factor SAMHD1 or transcriptional factor HLTF, respectively. Selective disruption of viral CRL4 (DCAF1) E3 ligase could be a promising antiviral strategy. Recently, we have determined that post-translational modification (neddylation) of Cullin-4 is required for the activation of Vpx-CRL4 (DCAF1) E3 ligase. However, the mechanism of Vpx/Vpr-CRL4 (DCAF1) E3 ligase assembly is still poorly understood...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28148784/different-expression-of-interferon-stimulated-genes-in-response-to-hiv-1-infection-in-dendritic-cells-based-on-their-maturation-state
#18
Esther Calonge, Mercedes Bermejo, Francisco Diez-Fuertes, Isabelle Mangeot, Nuria González, Mayte Coiras, Laura Jiménez Tormo, Javier García-Perez, Nathalie Dereuddre-Bosquet, Roger Le Grand, José Alcamí
Dendritic cells (DCs) are professional antigen-presenting cells whose functions are dependent on their degree of differentiation. In their immature state, DCs capture pathogens and migrate to the lymph nodes. During this process, DCs become resident mature cells specialized in antigen presentation. DCs are characterized by a highly limiting environment for human immunodeficiency virus type 1 (HIV-1) replication due to the expression of restriction factors such as SAMHD1 and APOBEC3G. However, uninfected DCs capture and transfer viral particles to CD4 lymphocytes through a trans-enhancement mechanism in which chemokines are involved...
April 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28122869/a-g1-like-state-allows-hiv-1-to-bypass-samhd1-restriction-in-macrophages
#19
Petra Mlcochova, Katherine A Sutherland, Sarah A Watters, Cosetta Bertoli, Rob Am de Bruin, Jan Rehwinkel, Stuart J Neil, Gina M Lenzi, Baek Kim, Asim Khwaja, Matthew C Gage, Christiana Georgiou, Alexandra Chittka, Simon Yona, Mahdad Noursadeghi, Greg J Towers, Ravindra K Gupta
An unresolved question is how HIV-1 achieves efficient replication in terminally differentiated macrophages despite the restriction factor SAMHD1. We reveal inducible changes in expression of cell cycle-associated proteins including MCM2 and cyclins A, E, D1/D3 in macrophages, without evidence for DNA synthesis or mitosis. These changes are induced by activation of the Raf/MEK/ERK kinase cascade, culminating in upregulation of CDK1 with subsequent SAMHD1 T592 phosphorylation and deactivation of its antiviral activity...
March 1, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28113112/interplay-between-hiv-1-innate-sensing-and-restriction-in-mucosal-dendritic-cells-balancing-defense-and-viral-transmission
#20
REVIEW
Nina Hertoghs, Teunis B H Geijtenbeek, Carla M S Ribeiro
Innate sensing of HIV-1 by dendritic cells (DCs) initiates cell-intrinsic signalling programs that direct virus restriction and antiviral defenses. These responses include the production of type I interferon (IFN) and a large number of IFN-stimulated genes (ISGs) with a broad spectrum of antiviral effector functions. Initial interactions of HIV-1 at the mucosal surfaces with DC-expressed innate immune factors including cGAS, TRIM5α and SAMHD1 are predictive of viraemia, inflammation and disease pathogenesis...
January 20, 2017: Current Opinion in Virology
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