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https://www.readbyqxmd.com/read/28814521/hiv-fusion-in-dendritic-cells-mainly-occurs-at-the-surface-and-is-limited-by-low-cd4-levels
#1
Lise Chauveau, Daniel Aaron Donahue, Blandine Monel, Francoise Porrot, Timothée Bruel, Lea Richard, Nicoletta Casartelli, Olivier Schwartz
HIV-1 poorly infects monocyte-derived dendritic cells (MDDCs). This is in a large part due to SAMHD1, which restricts viral reverse transcription. Pseudotyping HIV-1 with VSV-G strongly enhances infection, suggesting that earlier steps of viral replication, including fusion, are also inefficient in MDDCs. The site of HIV-1 fusion remains controversial and may depend on the cell type, with reports indicating that it occurs at the plasma membrane or contrarily, in an endocytic compartment. Here, we examined the pathways of HIV-1 entry in MDDCs...
August 16, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28803141/the-poly-proline-tail-of-sivmac-vpx-provides-gain-of-function-for-resistance-to-a-cryptic-proteasome-dependent-degradation-pathway
#2
Nannan Zhang, Haoran Guo, Jiaxin Yang, Guanchen Liu, Shuang Li, Siying Li, Dongyin Wang, Rui Li, Chang Shu, Hongmei Xu, Zhentong Wei, Honglan Huang, Songling Zhang, Pujun Gao, Shan Cen, Richard Markham, Yongsheng Wang, Xiao-Fang Yu, Wei Wei
The lentiviral accessory protein Vpx is critical for viral infection of myeloid cells and acts by hijacking CRL4(DCAF1) E3 ubiquitin ligase to induce the degradation of the host restriction factor SAMHD1. It has been observed that the sequences from HIV-2 and SIVsmm/SIVmac Vpx contain a poly-proline tail which is distinct from other SIV Vpx proteins. However, the role of this region in Vpx function is controversial. Herein, we found proteasome-dependent degradation of a Vpx mutant lacking the poly-proline tail in the nucleus in a CRL4(DCAF1) E3 ligase-independent fashion...
August 10, 2017: Virology
https://www.readbyqxmd.com/read/28793904/the-impact-of-p53-on-the-early-stage-replication-of-retrovirus
#3
Michaela Kinnetz, Faris Alghamdi, Michael Racz, Wenwei Hu, Binshan Shi
BACKGROUND: The function of p53 in cancer biology has been studied extensively, but its role in anti-retrovirus infection has been elusive for many years. The restriction of retrovirus early stage replication by p53 was investigated in this study. METHOD: VSV-G pseudotyped retrovirus with GFP reporter gene was used to infect both HCT116 p53(+/+) cells and its isogenic p53 knockout HCT116 p53(-/-) cells. The infection was detected by flow cytometry. Reverse transcription products were quantified by real time PCR...
August 9, 2017: Virology Journal
https://www.readbyqxmd.com/read/28685292/role-of-innate-genes-in-hiv-replication
#4
Kerstin Schott, Maximilian Riess, Renate König
Cells use an elaborate innate immune surveillance and defense system against virus infections. Here, we discuss recent studies that reveal how HIV-1 is sensed by the innate immune system. Furthermore, we present mechanisms on the counteraction of HIV-1. We will provide an overview how HIV-1 actively utilizes host cellular factors to avoid sensing. Additionally, we will summarize effectors of the innate response that provide an antiviral cellular state. HIV-1 has evolved passive mechanism to avoid restriction and to regulate the innate response...
July 8, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28586337/corrigendum-samhd1-is-a-biomarker-for-cytarabine-response-and-a-therapeutic-target-in-acute-myeloid-leukemia
#5
Constanze Schneider, Thomas Oellerich, Hanna-Mari Baldauf, Sarah-Marie Schwarz, Dominique Thomas, Robert Flick, Hanibal Bohnenberger, Lars Kaderali, Lena Stegmann, Anjali Cremer, Margarethe Martin, Julian Lohmeyer, Martin Michaelis, Veit Hornung, Christoph Schliemann, Wolfgang E Berdel, Wolfgang Hartmann, Eva Wardelmann, Federico Comoglio, Martin-Leo Hansmann, Alexander F Yakunin, Gerd Geisslinger, Philipp Ströbel, Nerea Ferreirós, Hubert Serve, Oliver T Keppler, Jindrich Cinatl
No abstract text is available yet for this article.
June 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28584254/whole-genome-sequencing-of-chronic-lymphocytic-leukemia-reveals-distinct-differences-in-the-mutational-landscape-between-ighv-mut-and-ighv-unmut-subgroups
#6
A Burns, R Alsolami, J Becq, A Timbs, D Bruce, P Robbe, D Vavoulis, M Cabes, H Dreau, J Taylor, S J L Knight, R Mansson, D Bentley, R Beekman, J I Martín-Subero, E Campo, R S Houlston, K E Ridout, A Schuh
Chronic lymphocytic leukemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole genome sequencing (WGS) analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding SNVs, CNVs and structural variants, regions of kataegis and mutation signatures between IgHV(mut) and IgHV(unmut) subtypes...
June 6, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28502830/with-me-or-against-me-tumor-suppressor-and-drug-resistance-activities-of-samhd1
#7
Nikolas Herold, Sean G Rudd, Kumar Sanjiv, Juliane Kutzner, Ida Hed Myrberg, Cynthia B J Paulin, Thale Kristin Olsen, Thomas Helleday, Jan-Inge Henter, Torsten Schaller
Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) is a (deoxy)guanosine triphosphate (dGTP/GTP)-activated deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase involved in cellular dNTP homoeostasis. Mutations in SAMHD1 have been associated with the hyperinflammatory disease Aicardi-Goutières syndrome (AGS). SAMHD1 also limits cells' permissiveness to infection with diverse viruses, including human immunodeficiency virus (HIV-1), and controls endogenous retroviruses...
May 11, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28486838/brain-microglial-cells-are-highly-susceptible-to-hiv-1-infection-and-spread
#8
Jennifer J Cenker, Ryan D Stultz, David McDonald
Macrophages are a target of human immunodeficiency virus type 1 (HIV-1) infection and may serve as an important reservoir of the virus in the body, particularly after depletion of CD4(+) T cells in HIV/AIDS. Recently, sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) was identified as the major restriction factor of HIV-1 infection in myeloid cells. SAMHD1 is targeted for proteolytic degradation by Vpx, a viral protein encoded by HIV-2 and many simian immunodeficiency viruses but not HIV-1...
June 26, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28475458/mda5-associated-neuroinflammation-and-the-singleton-merten-syndrome-two-faces-of-the-same-type-i-interferonopathy-spectrum
#9
Insa Buers, Gillian I Rice, Yanick J Crow, Frank Rutsch
In 1973, Singleton and Merten described a new syndrome in 2 female probands with aortic and cardiac valve calcifications, early loss of secondary dentition, and widened medullary cavities of the phalanges. In 1984, Aicardi and Goutières defined a phenotype resembling congenital viral infection with basal ganglia calcification and increased protein content in the cerebrospinal fluid. Between 2006 and 2012, mutations in 6 different genes were described to be associated with Aicardi-Goutières syndrome, specifically-TREX1, RNASEH2A, RNASEH2B, RNASEH2C, ADAR, and SAMHD1...
May 2017: Journal of Interferon & Cytokine Research
https://www.readbyqxmd.com/read/28444859/roles-of-samhd1-in-antiviral-defense-autoimmunity-and-cancer
#10
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
#11
Nikolas Herold, Sean G Rudd, Kumar Sanjiv, Juliane Kutzner, Julia Bladh, Cynthia B J Paulin, Thomas Helleday, Jan-Inge Henter, Torsten Schaller
Recently, we demonstrated that sterile α motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemia (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...
June 3, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28401188/samhd1-is-a-barrier-to-antimetabolite-based-cancer-therapies
#12
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
#13
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
#14
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...
May 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
#15
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
#16
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
#17
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...
July 2017: Proteins
https://www.readbyqxmd.com/read/28289923/tocilizumab-reverses-cerebral-vasculopathy-in-a-patient-with-homozygous-samhd1-mutation
#18
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...
June 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
#19
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
#20
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
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