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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
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
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)...
September 19, 2016: Neuropediatrics
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
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
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
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
Zhonghua Wang, Akash Bhattacharya, Jessica Villacorta, Felipe Diaz-Griffero, Dmitri N Ivanov
SAMHD1 is a deoxynucleotidetriphosphate (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...
August 26, 2016: Journal of Biological Chemistry
Roger Badia, Maria Pujantell, Eva Riveira-Muñoz, Teresa Puig, Javier Torres-Torronteras, Ramón Martí, Bonaventura Clotet, Rosa M Ampudia, Marta Vives-Pi, José A Esté, Ester Ballana
Macrophages are a heterogeneous cell population strongly influenced by differentiation stimuli that become susceptible to HIV-1 infection after inactivation of the restriction factor SAMHD1 by cyclin-dependent kinases (CDK). Here, we have used primary human monocyte-derived macrophages differentiated through different stimuli to evaluate macrophage heterogeneity on cell activation and proliferation and susceptibility to HIV-1 infection. Stimulation of monocytes with GM-CSF induces a non-proliferating macrophage population highly restrictive to HIV-1 infection, characterized by the upregulation of the G1/S-specific cyclin D2, known to control early steps of cell cycle progression...
August 2016: PLoS Pathogens
Muhammad Imran, Sobia Manzoor, Muhammad Saalim, Saleha Resham, Javed Ashraf, Aneela Javed, Ahmed Bilal Waqar
Human immunodeficiency virus (HIV) infection is a major health burden across the world which leads to the development of acquired immune deficiency syndrome (AIDS). This review article discusses the prevalence of HIV, its major routes of transmission, natural immunity, and evasion from the host immune system. HIV is mostly prevalent in Sub-Saharan Africa and low income countries. It is mostly transmitted by sharing syringe needles, blood transfusion, and sexual routes. The host immune system is categorized into three main types; the innate, the adaptive, and the intrinsic immune system...
October 2016: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
John L Goodier
Retrotransposons have generated about 40 % of the human genome. This review examines the strategies the cell has evolved to coexist with these genomic "parasites", focussing on the non-long terminal repeat retrotransposons of humans and mice. Some of the restriction factors for retrotransposition, including the APOBECs, MOV10, RNASEL, SAMHD1, TREX1, and ZAP, also limit replication of retroviruses, including HIV, and are part of the intrinsic immune system of the cell. Many of these proteins act in the cytoplasm to degrade retroelement RNA or inhibit its translation...
2016: Mobile DNA
Akash Bhattacharya, Zhonghua Wang, Tommy White, Cindy Buffone, Laura A Nguyen, Caitlin N Shepard, Baek Kim, Borries Demeler, Felipe Diaz-Griffero, Dmitri N Ivanov
SAMHD1, a dNTP triphosphohydrolase, contributes to interferon signaling and restriction of retroviral replication. SAMHD1-mediated retroviral restriction is thought to result from the depletion of cellular dNTP pools, but it remains controversial whether the dNTPase activity of SAMHD1 is sufficient for restriction. The restriction ability of SAMHD1 is regulated in cells by phosphorylation on T592. Phosphomimetic mutations of T592 are not restriction competent, but appear intact in their ability to deplete cellular dNTPs...
2016: Scientific Reports
Maria Pujantell, Roger Badia, Cristina Ramirez, Teresa Puig, Bonaventura Clotet, Ester Ballana, José A Esté, Eva Riveira-Muñoz
HIV-1 infection is thought to impair type I interferon (IFN-I) production in macrophages, a cell type that is also relatively resistant to HIV-1 cytotoxic effects. Here, we show that monocyte differentiation into macrophages by M-CSF led to cell proliferation and susceptibility to HIV-1 infection that induced cell cycle arrest and increased cell death. Established HIV-1 infection of monocyte-derived macrophages induced the upregulation of the pattern recognition receptors MDA5 and Rig-I that serve as virus sensors; production of interferon-β, and transcription of interferon-stimulated genes including CXCL10...
September 2016: Antiviral Research
Jonathan Maelfait, Anne Bridgeman, Adel Benlahrech, Chiara Cursi, Jan Rehwinkel
SAMHD1 is a restriction factor for HIV-1 infection. SAMHD1 mutations cause the autoinflammatory Aicardi-Goutières syndrome that is characterized by chronic type I interferon (IFN) secretion. We show that the spontaneous IFN response in SAMHD1-deficient cells and mice requires the cGAS/STING cytosolic DNA-sensing pathway. We provide genetic evidence that cell-autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of co-stimulatory markers...
August 9, 2016: Cell Reports
Nicholas J Matheson, Edward Jd Greenwood, Paul J Lehner
Evolutionary pressure has produced an 'arms race' between cellular restriction factors (limiting viral replication) and viral proteins (overcoming host restriction). The host factors SAMHD1 and SLFN1 patrol metabolic bottlenecks required for HIV replication. Conversely, the HIV accessory proteins Vpx, Vpu and Nef manipulate cellular metabolism to enable viral replication. Recent work identifying Vpu-mediated downregulation of the alanine transporter SNAT1 and Nef-mediated downregulation of the serine carriers SERINC3/5 has uncovered the importance of HIV manipulation of the amino acid supply...
August 2016: Current Opinion in Virology
Yasuo Ariumi
Long interspersed element type 1 (LINE-1, L1) is a mobile genetic element comprising about 17% of the human genome, encoding a newly identified ORF0 with unknown function, ORF1p with RNA-binding activity and ORF2p with endonuclease and reverse transcriptase activities required for L1 retrotransposition. L1 utilizes an endonuclease (EN) to insert L1 cDNA into target DNA, which induces DNA double-strand breaks (DSBs). The ataxia-telangiectasia mutated (ATM) is activated by DSBs and subsequently the ATM-signaling pathway plays a role in regulating L1 retrotransposition...
2016: Frontiers in Chemistry
Shen Yang, Yuan Zhan, Yanjun Zhou, Yifeng Jiang, Xuchen Zheng, Lingxue Yu, Wu Tong, Fei Gao, Liwei Li, Qinfeng Huang, Zhiyong Ma, Guangzhi Tong
SAMHD1 is a type I interferon (IFN) inducible host innate immunity restriction factor that inhibits an early step of the viral life cycle. The underlying mechanisms of SAMHD1 transcriptional regulation remains elusive. Here, we report that inducing SAMHD1 upregulation is part of an early intrinsic immune response via TLR3 and RIG-I/MDA5 agonists that ultimately induce the nuclear translocation of the interferon regulation factor 3 (IRF3) protein. Further studies show that IRF3 plays a major role in upregulating endogenous SAMHD1 expression in a mechanism that is independent of the classical IFN-induced JAK-STAT pathway...
2016: Scientific Reports
Jeongmin Ryoo, Sung-Yeon Hwang, Jongsu Choi, Changhoon Oh, Kwangseog Ahn
SAMHD1 plays diverse roles in innate immunity, autoimmune diseases and HIV restriction, but the mechanisms involved are still unclear. SAMHD1 has been reported to have both dNTPase and RNase activities. However, whether SAMHD1 possesses RNase activity remains highly controversial. Here, we found that, unlike conventional hydrolytic exoribonucleases, SAMHD1 requires inorganic phosphate to degrade RNA substrates and produces nucleotide diphosphates rather than nucleoside monophosphates, which indicated that SAMHD1 is a phosphorolytic but not hydrolytic 3'-5' exoribonuclease...
September 2, 2016: Biochemical and Biophysical Research Communications
Ayumi Kudoh, Kei Miyakawa, Satoko Matsunaga, Yuki Matsushima, Isao Kosugi, Hirokazu Kimura, Satoshi Hayakawa, Tatsuya Sawasaki, Akihide Ryo
Virus-host interactions play vital roles in viral replication and virus-induced pathogenesis. Viruses rely entirely upon host cells to reproduce progeny viruses; however, host factors positively or negatively regulate virus replication by interacting with viral proteins. The elucidation of virus-host protein interaction not only provides a better understanding of the molecular mechanisms by which host cells combat viral infections, but also facilitates the development of new anti-viral therapeutics. Identification of relevant host factors requires techniques that enable comprehensive characterization of virus-host protein interactions...
2016: Frontiers in Microbiology
Magdalena A Czubala, Katja Finsterbusch, Matthew O Ivory, J Paul Mitchell, Zahra Ahmed, Takatoshi Shimauchi, Richard O S Karoo, Sion A Coulman, Christopher Gateley, James C Birchall, Fabien P Blanchet, Vincent Piguet
Sterile alpha motif (SAM) and histidine-aspartic (HD) domains protein 1 (SAMHD1) was previously identified as a critical post-entry restriction factor to HIV-1 infection in myeloid dendritic cells. Here we show that SAMHD1 is also expressed in epidermis-isolated Langerhans cells (LC), but degradation of SAMHD1 does not rescue HIV-1 or vesicular stomatitis virus G-pseudotyped lentivectors infection in LC. Strikingly, using Langerhans cells model systems (mutz-3-derived LC, monocyte-derived LC [MDLC], and freshly isolated epidermal LC), we characterize previously unreported post-entry restriction activity to HIV-1 in these cells, which acts at HIV-1 reverse transcription, but remains independent of restriction factors SAMHD1 and myxovirus resistance 2 (MX2)...
October 2016: Journal of Investigative Dermatology
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