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https://www.readbyqxmd.com/read/29321964/introduction-of-h2c2-type-zinc-binding-residues-into-hiv-2-vpr-increases-its-expression-level
#1
Ryoko Koga, Minami Yamamoto, Halil Ibrahim Ciftci, Masami Otsuka, Mikako Fujita
Human immunodeficiency virus type 2 has two structurally similar proteins, Vpx and Vpr. Vpx degrades the host anti-viral protein SAMHD1 and is expressed at high levels, while Vpr is responsible for cell cycle arrest and is expressed at much lower levels. We constructed a Vpr mutant with a high level of expression by replacing the amino acids HHCR/HHCH with a putative H2C2-type zinc-binding site that is carried by Vpx. Our finding suggests that during the evolution of Vpr and Vpx, zinc-binding likely became a mechanism for regulating their expression levels...
January 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29321329/a-cyclin-binding-motif-in-human-samhd1-is-required-for-its-hiv-1-restriction-dntpase-activity-tetramer-formation-and-efficient-phosphorylation
#2
Corine St Gelais, Sun Hee Kim, Victoria V Maksimova, Olga Buzovetsky, Kirsten Knecht, Caitlin Shepard, Baek Kim, Yong Xiong, Li Wu
Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) regulates intracellular deoxynucleoside triphosphate (dNTP) levels and functions as a retroviral restriction factor through its dNTP triphosphohydrolase (dNTPase) activity. Human SAMHD1 interacts with cell cycle regulatory proteins cyclin A2, cyclin-dependent kinase 1 (CDK1), and CDK2. This interaction mediates phosphorylation of SAMHD1 at threonine 592 (T592), which negatively regulates HIV-1 restriction. We previously reported that the interaction is mediated, at least in part, through a cyclin-binding motif (RXL, aa...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29311560/a-central-role-for-pi3k-akt-signaling-pathway-in-linking-samhd1-deficiency-to-the-type-i-interferon-signature
#3
Changhoon Oh, Jeongmin Ryoo, Kiwon Park, Baek Kim, Michele B Daly, DongYeon Cho, Kwangseog Ahn
The autoimmune disorder Aicardi-Goutières syndrome (AGS) is characterized by a constitutive type I interferon response. SAMHD1 possesses both dNTPase and RNase activities and mutations in SAMHD1 cause AGS; however, how SAMHD1-deficiency causes the type I interferon response in patients with AGS remains unknown. Here, we show that endogenous RNA substrates accumulated in the absence of SAMHD1 act as a major immunogenic source for the type I interferon response. Reconstitution of SAMHD1-negative human cells with wild-type but not RNase-defective SAMHD1 abolishes spontaneous type I interferon induction...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29296946/latent-human-cytomegalovirus-enhances-hiv-1-infection-in-cd34-progenitor-cells
#4
Allen Ka Loon Cheung, Yiru Huang, Hau Yee Kwok, Min Chen, Zhiwei Chen
Individuals who have been preinfected by human cytomegalovirus (HCMV) are more prone to AIDS disease progression after subsequent HIV-1 infection but the underlying mechanism remains elusive. HCMV is a ubiquitous DNA virus that commonly establishes lifelong latent infection in CD34+ progenitor cells, where latency-specific HCMV genes may modulate host restriction to HIV-1 infection. To test this hypothesis, we studied progenitor cells that are known to resist replicative HIV-1 infection because of the intrinsic expression of host restriction factors...
January 24, 2017: Blood Advances
https://www.readbyqxmd.com/read/29274141/acquired-resistance-of-pten-deficient-cells-to-parp-inhibitor-and-ara-c-mediated-by-53bp1-loss-and-samhd1-overexpression
#5
Yu-Ting Wang, Bo Yuan, Hua-Dong Chen, Lin Xu, Yu-Nan Tian, Ao Zhang, Jin-Xue He, Ze-Hong Miao
With increasing uses of PARP inhibitors (PARPis) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the PTEN-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46~71.78-fold) to all 5 PARPis including niraparib and rucaparib and showed higher degrees of resistance to the PARPis to which the parental cells were more sensitive...
December 22, 2017: Cancer Science
https://www.readbyqxmd.com/read/29249320/the-expression-profile-of-sterile-alpha-motif-and-histidine-aspartate-domain-containing-protein-1-samhd1-in-feline-tissues
#6
Peyman Asadian, Gillian Finnie, Dorothee Bienzle
SAMHD1 restricts lentiviruses by limiting availability of deoxynucleoside triphosphates for reverse transcription. HIV-2 and SIV have virion-associated proteins to counteract SAMHD1. Cats have an ortholog to human SAMHD1 and the FIV is restricted by human SAMHD1, but expression of feline SAMHD1 is unknown. Using a whole-body tissue microarray consisting of 24 tissues for immunohistochemistry, SAMHD1 expression was identified in a wide range of cat tissues. SAMHD1 was most strongly expressed in skin and mucosal epithelium, and in hemolymphatic and spermatogenic tissues...
January 2018: Veterinary Immunology and Immunopathology
https://www.readbyqxmd.com/read/29239743/phenotypic-and-molecular-spectrum-of-aicardi-gouti%C3%A3-res-syndrome-a-study-of-24-patients
#7
Fuad Al Mutairi, Majid Alfadhel, Marwan Nashabat, Ayman W El-Hattab, Tawfeg Ben-Omran, Jozef Hertecant, Wafaa Eyaid, Rehab Ali, Ali Alasmari, Majdi Kara, Waleed Al-Twaijri, Rana Filimban, Abduljabbar Alshenqiti, Mohammed Al-Owain, Eissa Faqeih, Fowzan S Alkuraya
BACKGROUND: Aicardi-Goutières syndrome is a rare genetic neurological disorder with variable clinical manifestations. Molecular detection of specific mutations is required to confirm the diagnosis. The aim of this retrospective study was to review the clinical and molecular diagnostic findings in 24 cases of Aicardi-Goutières syndrome presenting in childhood in the Arab population. MATERIALS AND METHODS: We reviewed the records of 24 patients from six tertiary hospitals in different Arab countries...
October 5, 2017: Pediatric Neurology
https://www.readbyqxmd.com/read/29176984/the-dynamic-interplay-between-hiv-1-samhd1-and-the-innate-antiviral-response
#8
REVIEW
Jenna M Antonucci, Corine St Gelais, Li Wu
The innate immune response constitutes the first cellular line of defense against initial HIV-1 infection. Immune cells sense invading virus and trigger signaling cascades that induce antiviral defenses to control or eliminate infection. Professional antigen-presenting cells located in mucosal tissues, including dendritic cells and macrophages, are critical for recognizing HIV-1 at the site of initial exposure. These cells are less permissive to HIV-1 infection compared to activated CD4+ T-cells, which is mainly due to host restriction factors that serve an immediate role in controlling the establishment or spread of viral infection...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29100097/monogenic-lupus-it-s-all-new
#9
REVIEW
Patricia Costa-Reis, Kathleen E Sullivan
Monogenic lupus is rare, but its study has contributed immensely to a better understanding of the pathogenesis of systemic lupus erythematosus. The first forms identified were inherited complement deficiencies, which predisposed to lupus due to impaired tolerance, and aberrant clearance of apoptotic bodies and immune complexes. In recent years, several new monogenic disorders with a lupus-like phenotype have been described. These include forms that affect nucleic acid repair, degradation and sensing (TREX1, DNASE1L3), the type I interferon (IFN) pathway (SAMHD1, RNASEH2ABC, ADAR1, IFIH1, ISG15, ACP5, TMEM173) and B cell development checkpoints (PRKCD; RAG2)...
October 27, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28978134/samhd1-acetylation-enhances-its-deoxynucleotide-triphosphohydrolase-activity-and-promotes-cancer-cell-proliferation
#10
Eun Ji Lee, Ji Hae Seo, Ji-Hyeon Park, Tam Thuy Lu Vo, Sunho An, Sung-Jin Bae, Hoang Le, Hye Shin Lee, Hee-Jun Wee, Danbi Lee, Young-Hwa Chung, Jeong A Kim, Myoung-Kuk Jang, Soo Hyung Ryu, Ensil Yu, Se Hwan Jang, Zee Yong Park, Kyu-Won Kim
SAM domain and HD domain containing protein 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase (dNTPase) that inhibits retroviruses by depleting intracellular deoxynucleotide triphosphates (dNTPs) in non-cycling myeloid cells. Although SAMHD1 is expressed ubiquitously throughout the human body, the molecular mechanisms regulating its enzymatic activity and function in non-immune cells are relatively unexplored. Here, we demonstrate that the dNTPase activity of SAMHD1 is regulated by acetylation, which promotes cell cycle progression in cancer cells...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28977405/genome-scale-detection-of-positive-selection-in-nine-primates-predicts-human-virus-evolutionary-conflicts
#11
Robin van der Lee, Laurens Wiel, Teunis J P van Dam, Martijn A Huynen
Hotspots of rapid genome evolution hold clues about human adaptation. We present a comparative analysis of nine whole-genome sequenced primates to identify high-confidence targets of positive selection. We find strong statistical evidence for positive selection in 331 protein-coding genes (3%), pinpointing 934 adaptively evolving codons (0.014%). Our new procedure is stringent and reveals substantial artefacts (20% of initial predictions) that have inflated previous estimates. The final 331 positively selected genes (PSG) are strongly enriched for innate and adaptive immunity, secreted and cell membrane proteins (e...
October 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28969870/samhd1-sheds-moonlight-on-dna-double-strand-break-repair
#12
Maria Jose Cabello-Lobato, Siyue Wang, Christine Katrin Schmidt
SAMHD1 (sterile α motif and histidine (H) aspartate (D) domain-containing protein 1) is known for its antiviral activity of hydrolysing deoxynucleotides required for virus replication. Daddacha et al. identify a hydrolase-independent, moonlighting function of SAMHD1 that facilitates homologous recombination of DNA double-strand breaks (DSBs) by promoting recruitment of C-terminal binding protein interacting protein (CTIP), a DNA-end resection factor, to damaged DNA. These findings could benefit anticancer treatment...
September 29, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28956603/allosteric-signal-transduction-in-hiv-1-restriction-factor-samhd1-proceeds-via-reciprocal-handshake-across-monomers
#13
Kajwal Kumar Patra, Akash Bhattacharya, Swati Bhattacharya
The sterile alpha motif and histidine-aspartate domain-containing protein 1 (or SAMHD1), a human dNTP-triphosphohydrolase, contributes to HIV-1 restriction in select terminally differentiated cells of the immune system. The catalytically active form of the protein is an allosterically triggered tetramer, whose HIV-1 restriction properties are attributed to its dNTP-triphosphohydrolase activity. The tetramer itself is assembled by a GTP/dNTP combination. This enzyme uses the strategy of deoxynucleotide starvation, which is thought to prevent effective reverse transcription of the retroviral genome-hence, restricting HIV-1 propagation...
October 23, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28953327/t-cells-with-low-cd2-levels-express-reduced-restriction-factors-and-are-preferentially-infected-in-therapy-na%C3%A3-ve-chronic-hiv-1-patients
#14
Sebastian Bolduan, Herwig Koppensteiner, Ramona Businger, Stephanie Rebensburg, Christine Kunze, Ruth Brack-Werner, Rika Draenert, Michael Schindler
INTRODUCTION: Restriction factors (RFs) suppress HIV-1 in cell lines and primary cell models. Hence, RFs might be attractive targets for novel antiviral strategies, but their importance for virus control in vivo is controversial. METHODS: We profiled the expression of RFs in primary blood-derived mononuclear cells (PBMC) from therapy-naïve HIV-1 patients and quantified infection. RESULTS: Overall, there was no correlation between individual RF expression and HIV-1 status in total PBMC...
September 19, 2017: Journal of the International AIDS Society
https://www.readbyqxmd.com/read/28935667/upregulation-of-human-endogenous-retrovirus-k-is-linked-to-immunity-and-inflammation-in-pulmonary-arterial-hypertension
#15
Toshie Saito, Kazuya Miyagawa, Shih-Yu Chen, Rasa Tamosiuniene, Lingli Wang, Orr Sharpe, Erik Samayoa, Daisuke Harada, Jan-Renier A J Moonen, Aiqin Cao, Pin-I Chen, Jan K Hennigs, Mingxia Gu, Caiyun G Li, Ryan D Leib, Dan Li, Christopher M Adams, Patricia A Del Rosario, Matthew Bill, Francois Haddad, Jose G Montoya, William H Robinson, Wendy J Fantl, Garry P Nolan, Roham T Zamanian, Mark R Nicolls, Charles Y Chiu, Maria E Ariza, Marlene Rabinovitch
BACKGROUND: Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic, or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue, and elevated cytokines have been related to PAH pathogenesis but without a clear understanding of how these abnormalities are initiated, perpetuated, and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies...
November 14, 2017: Circulation
https://www.readbyqxmd.com/read/28931685/p21-restricts-hiv-1-in-monocyte-derived-dendritic-cells-through-the-reduction-of-deoxynucleoside-triphosphate-biosynthesis-and-regulation-of-samhd1-antiviral-activity
#16
Jose Carlos Valle-Casuso, Awatef Allouch, Annie David, Gina M Lenzi, Lydia Studdard, Françoise Barré-Sinoussi, Michaela Müller-Trutwin, Baek Kim, Gianfranco Pancino, Asier Sáez-Cirión
HIV-1 infection of noncycling cells, such as dendritic cells (DCs), is impaired due to limited availability of deoxynucleoside triphosphates (dNTPs), which are needed for HIV-1 reverse transcription. The levels of dNTPs are tightly regulated during the cell cycle and depend on the balance between dNTP biosynthesis and degradation. SAMHD1 potently blocks HIV-1 replication in DCs, although the underlying mechanism is still unclear. SAMHD1 has been reported to be able to degrade dNTPs and viral nucleic acids, which may both hamper HIV-1 reverse transcription...
December 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28884867/uncovering-allostery-and-regulation-in-samhd1-through-molecular-dynamics-simulations
#17
Kajwal Kumar Patra, Akash Bhattacharya, Swati Bhattacharya
No abstract text is available yet for this article.
October 2017: Proteins
https://www.readbyqxmd.com/read/28871089/cd81-association-with-samhd1-enhances-hiv-1-reverse-transcription-by-increasing-dntp-levels
#18
Vera Rocha-Perugini, Henar Suárez, Susana Álvarez, Soraya López-Martín, Gina M Lenzi, Felipe Vences-Catalán, Shoshana Levy, Baek Kim, María A Muñoz-Fernández, Francisco Sánchez-Madrid, Maria Yáñez-Mó
In this study, we report that the tetraspanin CD81 enhances human immunodeficiency virus (HIV)-1 reverse transcription in HIV-1-infected cells. This is enabled by the direct interaction of CD81 with the deoxynucleoside triphosphate phosphohydrolase SAMHD1. This interaction prevents endosomal accumulation and favours the proteasome-dependent degradation of SAMHD1. Consequently, CD81 depletion results in SAMHD1 increased expression, decreasing the availability of deoxynucleoside triphosphates (dNTP) and thus HIV-1 reverse transcription...
November 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28851465/samhd1-mutations-are-also-responsible-for-aicardi-gouti%C3%A3-res-in-the-cree-population
#19
Ashraf Kharrat, Jennifer MacKenzie, Sunita Venkateswaran
No abstract text is available yet for this article.
August 30, 2017: Canadian Journal of Neurological Sciences. le Journal Canadien des Sciences Neurologiques
https://www.readbyqxmd.com/read/28844088/familial-chilblain-lupus-what-can-we-learn-from-type-i-interferonopathies
#20
REVIEW
Christoph Fiehn
PURPOSE OF REVIEW: Familial chilblain lupus belongs to the group of type I interferonopathies and is characterized by typical skin manifestations and acral ischaemia. This review aims to give an overview of clinical signs and the pathophysiological mechanisms. RECENT FINDINGS: There are several mutations that can lead to this autosomal dominant disease. Most frequent is a mutation of the gene for TREX-1. However, as well cases of families with mutations in the SAMHD1 gene and, recently, with one for the gene that codes for the protein stimulator of interferon genes have been described...
August 26, 2017: Current Rheumatology Reports
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