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https://www.readbyqxmd.com/read/29614221/dynamics-conformational-entropy-and-frustration-in-protein-protein-interactions-involving-an-intrinsically-disordered-protein-domain
#1
Ida Lindström, Jakob Dogan
Intrinsically disordered proteins (IDPs) are abundant in the eukaryotic proteome. However, little is known about the role of sub-nanosecond dynamics and the conformational entropy that it represents in protein-protein interactions involving IDPs. Using NMR side chain and backbone relaxation, stopped-flow kinetics, ITC, and computational studies, we have here characterized the interaction between the globular TAZ1 domain of CREB binding protein, and the intrinsically disordered transactivation domain of STAT2 (TAD-STAT2)...
April 3, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29581268/irf9-and-unphosphorylated-stat2-cooperate-with-nf-%C3%AE%C2%BAb-to-drive-il6-expression
#2
Jing Nan, Yuxin Wang, Jinbo Yang, George R Stark
In response to IFNβ, the IL6 gene is activated, modestly at early times by ISGF3 (IRF9 plus tyrosine-phosphorylated STATs 1 and 2), and strongly at late times by U-ISGF3 (IRF9 plus U-STATs 1 and 2, lacking tyrosine phosphorylation). A classical IFN-stimulated response element (ISRE) at -1,513 to -1,526 in the human IL6 promoter is required. Pretreating cells with IFNβ or increasing the expression of U-STAT2 and IRF9 exogenously greatly enhances IL6 expression in response to the classical NF-κB activators IL1, TNF, and LPS...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29580840/hiv-1-promotes-the-degradation-of-components-of-the-type-1-ifn-jak-stat-pathway-and-blocks-anti-viral-isg-induction
#3
Siobhan Gargan, Suaad Ahmed, Rebecca Mahony, Ciaran Bannan, Silvia Napoletano, Cliona O'Farrelly, Persephone Borrow, Colm Bergin, Nigel J Stevenson
Anti-retroviral therapy successfully suppresses HIV-1 infection, but fails to provide a cure. During infection Type 1 IFNs normally play an essential role in viral clearance, but in vivo IFN-α only has a modest impact on HIV-1 infection, suggesting its possible targeting by HIV. Here, we report that the HIV protein, Vif, inhibits effective IFN-α signalling via degradation of essential JAK/STAT pathway components. We found that STAT1 and STAT3 are specifically reduced in HEK293T cells expressing Vif and that full length, infectious HIV-1 IIIB strain promotes their degradation in a Vif-dependent manner...
March 9, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29572905/infection-with-a-brazilian-isolate-of-zika-virus-generates-rig-i-stimulatory-rna-and-the-viral-ns5-protein-blocks-type-i-ifn-induction-and-signalling
#4
Jonny Hertzog, Antonio Gregorio Dias Junior, Rachel E Rigby, Claire L Donald, Alice Mayer, Erdinc Sezgin, Chaojun Song, Boquan Jin, Philip Hublitz, Christian Eggeling, Alain Kohl, Jan Rehwinkel
Zika virus (ZIKV) is a major public health concern in the Americas. We report that ZIKV infection and RNA extracted from ZIKV infected cells potently activated the induction of type I interferons (IFNs). This effect was fully dependent on the mitochondrial antiviral signalling protein (MAVS), implicating RIG-I-like receptors (RLRs) as upstream sensors of viral RNA. Indeed, RIG-I and the related RNA sensor MDA5 contributed to type I IFN induction in response to RNA from infected cells. We found that ZIKV NS5 from a recent Brazilian isolate blocked type I IFN induction downstream of RLRs and also inhibited type I IFN receptor (IFNAR) signalling...
March 23, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29572894/regulatory-gene-network-from-a-genome-wide-association-study-for-sow-lifetime-productivity-traits
#5
J-H Kang, E-A Lee, K-C Hong, J-M Kim
Among swine reproductive traits, sow lifetime productivity (SLP) is considered a profitable trait in commercial pig farming. Notably, longevity and efficiency in SLP can be adopted as the key phenotype representing SLP. In this study, we conducted a co-association network analysis using results from a genome-wide association study for SLP-related traits. A total of 656 purebred Landrace female pigs were genotyped using a 60K SNP array. Significantly associated SNPs identified from the GWAS were annotated for the specific genes...
March 23, 2018: Animal Genetics
https://www.readbyqxmd.com/read/29519508/modulation-of-type-i-interferon-signaling-by-african-swine-fever-virus-asfv-of-different-virulence-l60-and-nhv-in-macrophage-host-cells
#6
Raquel Portugal, Alexandre Leitão, Carlos Martins
ASFV causes an important disease of domestic swine and wild boar. Currently no vaccine is available, highlighting the necessity to understand ASFV modulation of innate immune responses in natural host cells. With this aim, macrophage cultures enriched in SWC9 and CD163 differentiation markers were infected in parallel with high virulent ASFV/L60 and low virulent ASFV/NHV, the latter lacking MGF 360 and 505/530 genes associated with type I interferon (IFN I) control. IFN I production and signaling were studied after completion of the viral cycles...
March 2018: Veterinary Microbiology
https://www.readbyqxmd.com/read/29504848/signalling-pathways-identified-in-salivary-glands-from-primary-sj%C3%A3-gren-s-syndrome-patients-reveal-enhanced-adipose-tissue-development
#7
Lara A Aqrawi, Janicke Liaaen Jensen, Gunnvor Øijordsbakken, Ann-Kristin Ruus, Ståle Nygård, Marit Holden, Roland Jonsson, Hilde Kanli Galtung, Kathrine Skarstein
A characteristic feature of primary Sjögren's syndrome (pSS) is the destruction of salivary and lacrimal glands mediated by mononuclear cell infiltration. Adipocytes can also occupy a large portion of the salivary gland (SG) tissue area, although little is known about their significance in pSS. We have previously investigated adipose tissue infiltration in SG biopsies from pSS patients and non-SS sicca controls. Our findings indicated the distinct incidence of adipose tissue replacement in pSS patients, where adipocytes were detected in interleukin (IL) 6 rich regions...
March 5, 2018: Autoimmunity
https://www.readbyqxmd.com/read/29497123/functional-innate-immunity-restricts-hepatitis-c-virus-infection-in-induced-pluripotent-stem-cell-derived-hepatocytes
#8
Anja Schöbel, Kathrin Rösch, Eva Herker
Knowledge of activation and interplay between the hepatitis C virus (HCV) and the hosts' innate immunity is essential to understanding the establishment of chronic HCV infection. Human hepatoma cell lines, widely used as HCV cell culture system, display numerous metabolic alterations and a defective innate immunity, hindering the detailed study of virus-host interactions. Here, we analysed the suitability of induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) as a physiologically relevant model to study HCV replication in vitro...
March 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29456540/kallikrein-kinin-system-suppresses-type-i-interferon-responses-a-novel-pathway-of-interferon-regulation
#9
Alecia Seliga, Michael Hweemoon Lee, Nicole C Fernandes, Viviana Zuluaga-Ramirez, Marta Didukh, Yuri Persidsky, Raghava Potula, Stefania Gallucci, Uma Sriram
The Kallikrein-Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin-converting enzyme (ACE), and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand), or recombinant IFN-α to induce interferon-stimulated genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein), or captopril (an ACE inhibitor)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29441069/interleukin-6-and-interferon-%C3%AE-signaling-via-jak1-stat-differentially-regulate-oncolytic-versus-cytoprotective-antiviral-states
#10
Oded Danziger, Tal Pupko, Eran Bacharach, Marcelo Ehrlich
Malignancy-induced alterations to cytokine signaling in tumor cells differentially regulate their interactions with the immune system and oncolytic viruses. The abundance of inflammatory cytokines in the tumor microenvironment suggests that such signaling plays key roles in tumor development and therapy efficacy. The JAK-STAT axis transduces signals of interleukin-6 (IL-6) and interferons (IFNs), mediates antiviral responses, and is frequently altered in prostate cancer (PCa) cells. However, how activation of JAK-STAT signaling with different cytokines regulates interactions between oncolytic viruses and PCa cells is not known...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29437254/crispr-cas9-knockout-of-usp18-enhances-type-i-ifn-responsiveness-and-restricts-hiv-1-infection-in-macrophages
#11
Jared P Taylor, Melanie N Cash, Katherine E Santostefano, Mahito Nakanishi, Naohiro Terada, Mark A Wallet
The IFN-stimulated gene ubiquitin-specific proteinase 18 (USP18) encodes a protein that negatively regulates T1 IFN signaling via stearic inhibition of JAK1 recruitment to the IFN-α receptor 2 subunit (IFNAR2). Here, we demonstrate that USP18 expression is induced by HIV-1 in a T1 IFN-dependent manner. Experimental depletion of USP18 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing results in a significant restriction of HIV-1 replication in an induced pluripotent stem cell (iPSC)-derived macrophage model...
February 13, 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29435494/tick-borne-encephalitis-virus-vaccine-induced-human-antibodies-mediate-negligible-enhancement-of-zika-virus-infection-in-vitro-and-in-a-mouse-model
#12
James Duehr, Silviana Lee, Gursewak Singh, Gregory A Foster, David Krysztof, Susan L Stramer, Maria C Bermúdez González, Eva Menichetti, Robert Geretschläger, Christian Gabriel, Viviana Simon, Jean K Lim, Florian Krammer
Recent reports in the scientific literature have suggested that anti-dengue virus (DENV) and anti-West Nile virus (WNV) immunity exacerbates Zika virus (ZIKV) pathogenesis in vitro and in vivo in mouse models. Large populations of immune individuals exist for a related flavivirus (tick-borne encephalitis virus [TBEV]), due to large-scale vaccination campaigns and endemic circulation throughout most of northern Europe and the southern Russian Federation. As a result, the question of whether anti-TBEV immunity can affect Zika virus pathogenesis is a pertinent one...
January 2018: MSphere
https://www.readbyqxmd.com/read/29434723/screening-for-key-genes-and-transcription-factors-in-ankylosing-spondylitis-by-rna-seq
#13
Zhongyang Xu, Xiuyu Wang, Yanping Zheng
Ankylosing spondylitis (AS) is a chronic inflammatory arthritis and autoimmune disease, the etiology and pathogenesis of which remain largely unknown. In the present study, blood samples were harvested from patients with AS and from healthy volunteers as a normal control (NC) for RNA-sequencing. Differentially expressed genes (DEGs) in the AS group compared with the NC group were identified, and gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were subsequently performed...
February 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29416786/identification-of-differentially-expressed-genes-in-human-breast-cancer-cells-induced-by-4-hydroxyltamoxifen-and-elucidation-of-their-pathophysiological-relevance-and-mechanisms
#14
Qi Fang, Shuang Yao, Guanghua Luo, Xiaoying Zhang
While tamoxifen (TAM) is used for treating estrogen receptor (ER)a-positive breast cancer patients, its anti-breast cancer mechanisms are not completely elucidated. This study aimed to examine effects of 4-hydroxyltamoxifen (4-OH-TAM) on ER-positive (ER+) breast cancer MCF-7 cell growth and gene expression profiles. MCF-7 cell growth was inhibited by 4-OH-TAM dose-dependently with IC50 of 29 μM. 332 genes were up-regulated while 320 genes were down-regulated. The mRNA levels of up-regulated genes including STAT1, STAT2, EIF2AK2, TGM2, DDX58, PARP9, SASH1, RBL2 and USP18 as well as down-regulated genes including CCDN1, S100A9, S100A8, ANXA1 and PGR were confirmed by quantitative real-time PCR (qRT-PCR)...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416731/comparative-proteomics-as-a-tool-for-identifying-specific-alterations-within-interferon-response-pathways-in-human-glioblastoma-multiforme-cells
#15
Irina A Tarasova, Alesya V Tereshkova, Anna A Lobas, Elizaveta M Solovyeva, Alena S Sidorenko, Vladimir Gorshkov, Frank Kjeldsen, Julia A Bubis, Mark V Ivanov, Irina Y Ilina, Sergei A Moshkovskii, Peter M Chumakov, Mikhail V Gorshkov
An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where oncolytic virus therapy would be most effective. We quantified changes in protein abundances in two glioblastoma multiforme (GBM) cell lines that differ in the ability to induce resistance to vesicular stomatitis virus (VSV) infection in response to type I interferon (IFN) treatment...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29379210/axl-promotes-zika-virus-infection-in-astrocytes-by-antagonizing-type-i-interferon-signalling
#16
Jian Chen, Yi-Feng Yang, Yu Yang, Peng Zou, Jun Chen, Yongquan He, Sai-Lan Shui, Yan-Ru Cui, Ru Bai, Ya-Jun Liang, Yunwen Hu, Biao Jiang, Lu Lu, Xiaoyan Zhang, Jia Liu, Jianqing Xu
Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain-Barré syndrome1,2. While progress has been made in understanding the causal link between ZIKV infection and microcephaly3-9, the life cycle and pathogenesis of ZIKV are less well understood. In particular, there are conflicting reports on the role of AXL, a TAM family kinase receptor that was initially described as the entry receptor for ZIKV10-22. Here, we show that while genetic ablation of AXL protected primary human astrocytes and astrocytoma cell lines from ZIKV infection, AXL knockout did not block the entry of ZIKV...
January 29, 2018: Nature Microbiology
https://www.readbyqxmd.com/read/29379200/shared-genetic-effects-on-chromatin-and-gene-expression-indicate-a-role-for-enhancer-priming-in-immune-response
#17
Kaur Alasoo, Julia Rodrigues, Subhankar Mukhopadhyay, Andrew J Knights, Alice L Mann, Kousik Kundu, Christine Hale, Gordon Dougan, Daniel J Gaffney
Regulatory variants are often context specific, modulating gene expression in a subset of possible cellular states. Although these genetic effects can play important roles in disease, the molecular mechanisms underlying context specificity are poorly understood. Here, we identified shared quantitative trait loci (QTLs) for chromatin accessibility and gene expression in human macrophages exposed to IFNγ, Salmonella and IFNγ plus Salmonella. We observed that ~60% of stimulus-specific expression QTLs with a detectable effect on chromatin altered the chromatin accessibility in naive cells, thus suggesting that they perturb enhancer priming...
January 29, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29326301/prognostic-roles-of-signal-transducers-activators-of-transcription-family-in-human-breast-cancer
#18
Shuntao Wang, Lili Yu, Wei Shi, Xueqin Li, Lixiu Yu
Signal transducer and activator of transcription (STAT) family are critical transcription factors, which have been proved as prognostic predictors for a number of cancers. However, the prognostic roles of STAT family in breast cancer patients remain in dispute. In this study, we mined the 'Kaplan-Meier plotter' (KM plotter) online database to explore the prognostic roles of STAT family mRNA expression in breast cancer including overall survival (OS), progression-free survival (PFS), as well as post-progression survival (PPS)...
January 11, 2018: Bioscience Reports
https://www.readbyqxmd.com/read/29317535/structural-basis-of-stat2-recognition-by-irf9-reveals-molecular-insights-into-isgf3-function
#19
Srinivasan Rengachari, Silvia Groiss, Juliette M Devos, Elise Caron, Nathalie Grandvaux, Daniel Panne
Cytokine signaling through the JAK/STAT pathway controls multiple cellular responses including growth, survival, differentiation, and pathogen resistance. An expansion in the gene regulatory repertoire controlled by JAK/STAT signaling occurs through the interaction of STATs with IRF transcription factors to form ISGF3, a complex that contains STAT1, STAT2, and IRF9 and regulates expression of IFN-stimulated genes. ISGF3 function depends on selective interaction between IRF9, through its IRF-association domain (IAD), with the coiled-coil domain (CCD) of STAT2...
January 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29306151/enhancement-of-immune-response-of-piglets-to-pcv-2-vaccine-by-porcine-il-2-and-fusion-il-4-6-gene-entrapped-in-chitosan-nanoparticles
#20
Yi Chen, Tingyu Song, Yong-Le Xiao, Xiaoping Wan, Luyi Yang, Jinghai Li, Guangzhi Zeng, Pengfei Fang, Ze-Zhou Wang, Rong Gao
In order to develop a novel effective immunomodulator to enhance pig resistance against post-weaning multi systemic wasting syndrome (PMWS), a recombinant plasmid co-expressing pig interleukin-2 (IL-2) and fusion interleukin-4/6 (IL-4/6) genes, designated VRIL4/6-2, was constructed and encapsulated in chitosan (CS) nanoparticles prepared by the ionotropic gelation method. Then 21-day old piglets were divided into two groups and intramuscularly injected respectively with VPIL4/6-2-CS and saline along with the porcine circovirus-2 (PCV-2) vaccine...
April 2018: Research in Veterinary Science
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