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https://www.readbyqxmd.com/read/27922067/immune-activation-influences-samhd1-expression-and-vpx-mediated-samhd1-degradation-during-chronic-hiv-1-infection
#1
Weihui Fu, Chao Qiu, Mingzhe Zhou, Lingyan Zhu, Yu Yang, Chenli Qiu, Linxia Zhang, Xuan Xu, Ying Wang, Jianqing Xu, Xiaoyan Zhang
SAMHD1 restricts human immunodeficiency virus type 1 (HIV-1) replication in myeloid cells and CD4(+) T cells, while Vpx can mediate SAMHD1 degradation to promote HIV-1 replication. Although the restriction mechanisms of SAMHD1 have been well-described, SAMHD1 expression and Vpx-mediated SAMHD1 degradation during chronic HIV-1 infection were poorly understood. Flow cytometric analysis was used to directly visualize ex vivo, and after in vitro SIV-Vpx treatment, SAMHD1 expression in CD4(+) T cells and monocytes...
December 6, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27920203/a-highly-active-isoform-of-lentivirus-restriction-factor-samhd1-in-mouse
#2
Nicolin Bloch, Sabine Gläsker, Poojitha Sitaram, Henning Hofmann, Caitlin N Shepard, Megan L Schultz, Baek Kim, Nathaniel R Landau
The triphosphohydrolase SAMHD1 restricts HIV-1 replication in nondividing myeloid cells by depleting the dNTP pool, preventing reverse transcription. SAMHD1 is also reported to have ribonuclease activity that degrades the virus genomic RNA. Human SAMHD1 is regulated by phosphorylation of its carboxy-terminus at T592, which abrogates its antiviral function yet has only a small effect on its phosphohydrolase activity. In the mouse, SAMHD1 is expressed as two isoforms (ISF1 and ISF2) that differ at the carboxy-terminus due to alternative splicing of the last coding exon...
December 5, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27909056/interferons-induce-expression-of-samhd1-in-monocytes-through-downregulation-of-mir-181a-and-mir-30a
#3
Maximilan Riess, Nina V Fuchs, Adam Idica, Matthias Hamdorf, Egbert Flory, Irene Munk Pedersen, Renate König
SAMHD1 is a phosphohydrolase maintaining cellular dNTP homeostasis but also acts as a critical regulator in innate immune responses due to its antiviral activity and association with autoimmune disease leading to aberrant activation of interferon. SAMHD1 expression is differentially regulated by interferon in certain primary cells, but the underlying mechanism is not understood. Here, we report a detailed characterization of the promotor region, the 5' and 3' untranslated region (UTR) of SAMHD1, and the mechanism responsible for the cell-type dependent upregulation of SAMHD1 protein by interferon...
December 1, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27905985/tlr7-8-agonist-induces-a-post-entry-samhd1-independent-block-to-hiv-1-infection-of-monocytes
#4
Henning Hofmann, Bénédicte Vanwalscappel, Nicolin Bloch, Nathaniel R Landau
BACKGROUND: Monocytes, the primary myeloid cell-type in peripheral blood, are resistant to HIV-1 infection as a result of the lentiviral restriction factor SAMHD1. Toll-like receptors recognize microbial pathogen components, inducing the expression of antiviral host proteins and proinflammatory cytokines. TLR agonists that mimic microbial ligands have been found to have activity against HIV-1 in macrophages. The induction of restriction factors in monocytes by TLR agonist activation has not been well studied...
December 1, 2016: Retrovirology
https://www.readbyqxmd.com/read/27889686/microrna-181-contributes-to-downregulation-of-samhd1-expression-in-cd4-t-cells-derived-from-s%C3%A3-zary-syndrome-patients
#5
Rebecca Kohnken, Karthik M Kodigepalli, Anjali Mishra, Pierluigi Porcu, Li Wu
Sézary syndrome (SS) is a rare subtype of cutaneous T-cell lymphoma (CTCL) that is characterized by aggressive spread of neoplastic CD4+ T-cells from the skin into the bloodstream with metastasis to visceral organs. The deoxynucleoside triphosphohydrolase SAMHD1 is highly expressed in normal CD4+ T-cells, while its expression is down-regulated in CD4+ T-cells from SS patients. MicroRNA (miR) dysregulation is an important epigenetic mechanism in the pathogenesis and progression of SS. MiR-181 has been shown to inhibit SAMHD1 expression in cell lines and was identified as an important prognostic biomarker in CTCL...
November 17, 2016: Leukemia Research
https://www.readbyqxmd.com/read/27878450/mass-spectrometry-based-proteomics-profiling-of-human-monocytes
#6
Yong Zeng, Fei-Yan Deng, Wei Zhu, Lan Zhang, Hao He, Chao Xu, Qing Tian, Ji-Gang Zhang, Li-Shu Zhang, Hong-Gang Hu, Hong-Wen Deng
Human monocyte is an important cell type which is involved in various complex human diseases. To better understand the biology of human monocytes and facilitate further studies, we developed the first comprehensive proteome knowledge base specifically for human monocytes by integrating both in vivo and in vitro datasets. The top 2000 expressed genes from in vitro datasets and 779 genes from in vivo experiments were integrated into this study. Altogether, a total of 2237 unique monocyte-expressed genes were cataloged...
November 22, 2016: Protein & Cell
https://www.readbyqxmd.com/read/27824273/anti-inflammaging-effects-of-lactobacillus-brevis-ow38-in-aged-mice
#7
J-J Jeong, K A Kim, Y-J Hwang, M J Han, D-H Kim
In the present study, lactic acid bacteria (LAB) strains were collected from kimchi and were screened to isolate strains that inhibit lipopolysaccharide (LPS) production by Escherichia coli and p16 expression and nuclear factor-kappa B (NF-κB) activation in LPS-stimulated macrophages. Oral administration of Lactobacillus brevis OW38 (1×10(9) cfu/mouse) to aged mice (male, 18 months old) for 8 weeks reduced the LPS level in colon fluid and blood. In addition, OW38 treatment also reduced the ratio of Firmicutes or Proteobacteria to Bacteroidetes, which was significantly higher in aged mice than in young mice...
November 8, 2016: Beneficial Microbes
https://www.readbyqxmd.com/read/27815502/a-putative-cyclin-binding-motif-in-human-samhd1-contributes-to-protein-phosphorylation-localization-and-stability
#8
Corine St Gelais, Sun Hee Kim, Lingmei Ding, Jacob Yount, Dmitri Ivanov, Paul Spearman, Li Wu
Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian protein that regulates intracellular dNTP levels through its hydrolysis of dNTPs. SAMHD1 functions as an important retroviral restriction factor through a mechanism relying on its dNTPase activity. We and others have reported that human SAMHD1 interacts with the cell cycle regulatory proteins cyclin A, CDK1, and CDK2, which mediates phosphorylation of SAMHD1 at threonine 592 (T592), a post-translational modification that has been implicated in abrogating SAMHD1 restriction function and ability to form stable tetramers...
November 4, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27803699/phylogenetic-insights-into-the-functional-relationship-between-primate-lentiviral-reverse-transcriptase-and-accessory-proteins-vpx-vpr
#9
Yosuke Sakai, Naoya Doi, Yasuyuki Miyazaki, Akio Adachi, Masako Nomaguchi
The efficiency of reverse transcription to synthesize viral DNA in infected cells greatly influences replication kinetics of retroviruses. However, viral replication in non-dividing cells such as resting T cells and terminally differentiated macrophages is potently and kinetically restricted by a host antiviral factor designated SAMHD1 (sterile alpha motif and HD-domain containing protein 1). SAMHD1 reduces cellular deoxynucleoside triphosphate (dNTP) pools and affects viral reverse transcription step. Human immunodeficiency virus type 2 (HIV-2) and some simian immunodeficiency viruses (SIVs) have Vpx or Vpr to efficiently degrade SAMHD1...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27790625/the-feasibility-of-incorporating-vpx-into-lentiviral-gene-therapy-vectors
#10
Samantha A McAllery, Chantelle L Ahlenstiel, Kazuo Suzuki, Geoff P Symonds, Anthony D Kelleher, Stuart G Turville
While current antiretroviral therapy has significantly improved, challenges still remain in life-long targeting of HIV-1 reservoirs. Lentiviral gene therapy has the potential to deliver protective genes into the HIV-1 reservoir. However, inefficient reverse transcription (RT) occurs in HIV-1 reservoirs during lentiviral gene delivery. The viral protein Vpx is capable of increasing lentiviral RT by antagonizing the restriction factor SAMHD1. Incorporating Vpx into lentiviral vectors could substantially increase gene delivery into the HIV-1 reservoir...
2016: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/27775344/single-stranded-nucleic-acids-bind-to-the-tetramer-interface-of-samhd1-and-prevent-formation-of-the-catalytic-homotetramer
#11
Kyle J Seamon, Namandje N Bumpus, James T Stivers
Sterile Alpha Motif and HD Domain Protein 1 (SAMHD1) is a unique enzyme that has important roles in nucleic acid metabolism, viral restriction, and the pathogenesis of autoimmune diseases and cancer. Although much attention has been focused on its dNTP triphosphohydrolase activity in viral restriction and disease, SAMHD1 also binds to single-stranded RNA and DNA. Here we utilize a UV crosslinking method using 5-bromodeoxyuridine-substituted oligonucleotides coupled with high-resolution mass spectrometry (HRMS) to identify the binding site for single-stranded nucleic acids (ssNA) on SAMHD1...
October 24, 2016: Biochemistry
https://www.readbyqxmd.com/read/27758709/samhd1-polymorphisms-were-significantly-correlated-with-hiv-siv-virus-load-in-pbmc-from-chinese-rhesus-macaques-and-cynomolgus-macaques
#12
Dan-Dan He, Shao-Long Mao, Wei Wang, Ya-Bin Jin, Hui-Ling Zhang, Fei Ling
Background-Sterile alpha motif and histidine aspartate domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is one of the novel restriction factors that potently supresses HIV-1 infection in myeloid cells at an early stage in the viral replication cycle. SAMHD1 activity is blocked by the action of viral accessory protein x (Vpx), which targets and recruits SAMHD1 for proteasomal degradation, in the SIVsm/HIV-2 lineage. Objective-The impact of SAMHD1 polymorphisms on viral replication in Chinese-origin rhesus macaques (CR) and cynomolgus macaques of Vietnamese origin (CM) have not been reported until now...
October 18, 2016: Current HIV Research
https://www.readbyqxmd.com/read/27711067/reply-to-samhd1-mediated-hiv-1-restriction-in-cells-does-not-involve-ribonuclease-activity
#13
Jeongmin Ryoo, Sung-Yeon Hwang, Jongsu Choi, Changhoon Oh, Kwangseog Ahn
No abstract text is available yet for this article.
October 6, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27711056/samhd1-mediated-hiv-1-restriction-in-cells-does-not-involve-ribonuclease-activity
#14
Jenna M Antonucci, Corine St Gelais, Suresh de Silva, Jacob S Yount, Chenxiang Tang, Xiaoyun Ji, Caitlin Shepard, Yong Xiong, Baek Kim, Li Wu
No abstract text is available yet for this article.
October 6, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27643693/neurologic-phenotypes-associated-with-mutations-in-trex1-rnaseh2a-rnaseh2b-rnaseh2c-samhd1-adar1-and-ifih1-aicardi-gouti%C3%A3-res-syndrome-and-beyond
#15
John H Livingston, Yanick J Crow
The Aicardi-Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7)...
December 2016: Neuropediatrics
https://www.readbyqxmd.com/read/27604406/the-importance-of-chilblains-as-a-diagnostic-clue-for-mild-aicardi-gouti%C3%A3-res-syndrome
#16
Kevin Yarbrough, Calida Danko, Alfons Krol, Jonathan Zonana, Sabra Leitenberger
Aicardi-Goutières syndrome (AGS) is classically characterized by early-onset encephalopathy. However, in some cases, the presenting symptom of concern may actually be cutaneous rather than neurological, leading to the misdiagnosis of the condition. We report the case of three teenage siblings who presented with a lifetime history of chilblain lesions, only one of whom had notable neurologic deficits. Additional findings included acrocyanosis, Raynaud's phenomenon, low-pitch hoarse voice, headache, and arthritis...
September 8, 2016: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27588835/substrate-specificity-of-samhd1-triphosphohydrolase-activity-is-controlled-by-deoxyribonucleoside-triphosphates-and-phosphorylation-at-thr592
#17
Sunbok Jang, Xiaohong Zhou, Jinwoo Ahn
The sterile alpha motif (SAM) and histidine-aspartate (HD) domain containing protein 1 (SAMHD1) constitute a triphosphohydrolase that converts deoxyribonucleoside triphosphates (dNTPs) into deoxyribonucleosides and triphosphates. SAMHD1 exists in multiple states. The monomer and apo- or GTP-bound dimer are catalytically inactive. Binding of dNTP at allosteric site 2 (AS2), adjacent to GTP-binding allosteric site 1 (AS1), induces formation of the tetramer, the catalytically active form. We have developed an enzyme kinetic assay, tailored to control specific dNTP binding at each site, allowing us to determine the kinetic binding parameters of individual dNTPs at both the AS2 and catalytic sites for all possible combinations of dNTP binding at both sites...
October 4, 2016: Biochemistry
https://www.readbyqxmd.com/read/27571178/the-ddb1-dcaf1-vpr-ung2-crystal-structure-reveals-how-hiv-1-vpr-steers-human-ung2-toward-destruction
#18
Ying Wu, Xiaohong Zhou, Christopher O Barnes, Maria DeLucia, Aina E Cohen, Angela M Gronenborn, Jinwoo Ahn, Guillermo Calero
The HIV-1 accessory protein Vpr is required for efficient viral infection of macrophages and promotion of viral replication in T cells. Vpr's biological activities are closely linked to the interaction with human DCAF1, a cellular substrate receptor of the Cullin4-RING E3 ubiquitin ligase (CRL4) of the host ubiquitin-proteasome-mediated protein degradation pathway. The molecular details of how Vpr usurps the protein degradation pathway have not been delineated. Here we present the crystal structure of the DDB1-DCAF1-HIV-1-Vpr-uracil-DNA glycosylase (UNG2) complex...
October 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27566796/familial-chilblain-lupus-due-to-a-gain-of-function-mutation-in-sting
#19
Nadja König, Christoph Fiehn, Christine Wolf, Max Schuster, Emanuel Cura Costa, Victoria Tüngler, Hugo Ariel Alvarez, Osvaldo Chara, Kerstin Engel, Raphaela Goldbach-Mansky, Claudia Günther, Min Ae Lee-Kirsch
OBJECTIVES: Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. METHODS: Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-β reporter and Western blotting...
August 26, 2016: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/27566548/allosteric-activation-of-samhd1-protein-by-deoxynucleotide-triphosphate-dntp-dependent-tetramerization-requires-dntp-concentrations-that-are-similar-to-dntp-concentrations-observed-in-cycling-t-cells
#20
Zhonghua Wang, Akash Bhattacharya, Jessica Villacorta, Felipe Diaz-Griffero, Dmitri N Ivanov
SAMHD1 is a dNTP hydrolase, whose activity is required for maintaining low dNTP concentrations in non-cycling T cells, dendritic cells, and macrophages. SAMHD1-dependent dNTP depletion is thought to impair retroviral replication in these cells, but the relationship between the dNTPase activity and retroviral restriction is not fully understood. In this study, we investigate allosteric activation of SAMHD1 by deoxynucleotide-dependent tetramerization and measure how the lifetime of the enzymatically active tetramer is affected by different dNTP ligands bound in the allosteric site...
October 7, 2016: Journal of Biological Chemistry
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