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https://www.readbyqxmd.com/read/27911820/map4-regulated-dynein-dependent-trafficking-of-btn3a1-controls-the-tbk1-irf3-signaling-axis
#1
Minji Seo, Seong-Ok Lee, Ji-Hoon Kim, Yujin Hong, Seongchan Kim, Yeumin Kim, Dal-Hee Min, Young-Yun Kong, Jinwook Shin, Kwangseog Ahn
The innate immune system detects viral nucleic acids and induces type I interferon (IFN) responses. The RNA- and DNA-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor IFN-regulatory factor 3 (IRF3). Activation of the IFN signaling pathway is known to trigger the redistribution of key signaling molecules to punctate perinuclear structures, but the mediators of this spatiotemporal regulation have yet to be defined. Here we identify butyrophilin 3A1 (BTN3A1) as a positive regulator of nucleic acid-mediated type I IFN signaling...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27906974/in-silico-knockout-studies-of-xenophagic-capturing-of-salmonella
#2
Jennifer Scheidel, Leonie Amstein, Jörg Ackermann, Ivan Dikic, Ina Koch
The degradation of cytosol-invading pathogens by autophagy, a process known as xenophagy, is an important mechanism of the innate immune system. Inside the host, Salmonella Typhimurium invades epithelial cells and resides within a specialized intracellular compartment, the Salmonella-containing vacuole. A fraction of these bacteria does not persist inside the vacuole and enters the host cytosol. Salmonella Typhimurium that invades the host cytosol becomes a target of the autophagy machinery for degradation...
December 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27892983/association-of-mutations-in-tbk1-with-sporadic-and-familial-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia
#3
Axel Freischmidt, Kathrin Müller, Albert C Ludolph, Jochen H Weishaupt, Peter M Andersen
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic...
November 21, 2016: JAMA Neurology
https://www.readbyqxmd.com/read/27881886/tank-binding-kinase-1-tbk1-gene-and-open-angle-glaucomas-an-american-ophthalmological-society-thesis
#4
John H Fingert, Alan L Robin, Todd E Scheetz, Young H Kwon, Jeffrey M Liebmann, Robert Ritch, Wallace L M Alward
PURPOSE: To investigate the role of TANK-binding kinase 1 (TBK1) gene copy-number variations (ie, gene duplications and triplications) in the pathophysiology of various open-angle glaucomas. METHODS: In previous studies, we discovered that copy-number variations in the TBK1 gene are associated with normal-tension glaucoma. Here, we investigated the prevalence of copy-number variations in cohorts of patients with other open-angle glaucomas-juvenile-onset open-angle glaucoma (n=30), pigmentary glaucoma (n=209), exfoliation glaucoma (n=225), and steroid-induced glaucoma (n=79)-using a quantitative polymerase chain reaction assay...
August 2016: Transactions of the American Ophthalmological Society
https://www.readbyqxmd.com/read/27878525/genetics-of-frontotemporal-dementia
#5
REVIEW
Diana A Olszewska, Roisin Lonergan, Emer M Fallon, Tim Lynch
Frontotemporal dementia (FTD) is the second most common cause of dementia following Alzheimer's disease (AD). Between 20 and 50% of cases are familial. Mutations in MAPT, GRN and C9orf72 are found in 60% of familial FTD cases. C9orf72 mutations are the most common and account for 25%. Rarer mutations (<5%) occur in other genes such as VPC, CHMP2B, TARDP, FUS, ITM2B, TBK1 and TBP. The diagnosis is often challenging due to symptom overlap with AD and other conditions. We review the genetics, clinical presentations, neuroimaging, neuropathology, animal studies and therapeutic trials in FTD...
December 2016: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/27859049/lps-primed-heterotolerant-dendritic-cells-suppress-experimental-autoimmune-uveoretintitis-by-multiple-mechanisms
#6
Izabela P Klaska, Elizabeth Muckersie, Cristina Martin-Granados, Maria Christofi, John V Forrester
Exposure of bone marrow derived dendritic cells (BMDC) to high dose ultrapure lipopolysaccharide for 24 hours (h) (LPS-primed BMDC) enhances their potency in preventing inter-photoreceptor retinoid binding protein (IRBP): complete Freund's adjuvant (CFA)-induced experimental autoimmune uveoretinitis (EAU). LPS-primed BMDC are refractory to further exposure to LPS (= endotoxin tolerance, ET), evidenced here by decreased phosphorylation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK) as well as impaired nuclear translocation of nuclear factor κB (NF-κB) and IRF3, resulting in reduced tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-12 and interferon beta (IFN-β) secretion...
November 15, 2016: Immunology
https://www.readbyqxmd.com/read/27797401/a-novel-function-of-tbk1-as-a-target-of-cdon-in-oligodendrocyte-differentiation-and-myelination
#7
Li-Chun Wang, Timothy E Kennedy, Guillermina Almazan
During central nervous system development, oligodendrocyte progenitors elaborate multiple branched processes to contact axons and initiate myelination. Using cultured primary rat oligodendrocytes (OLGs), we have recently demonstrated that a cell surface protein belonging to the immunoglobulin superfamily, Cdon, is important in initiating OLG differentiation and axon myelination by promoting the formation of branched cellular processes; however, the molecular mechanism by which Cdon regulates OLG differentiation is not known...
October 31, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27776110/e3-ubiquitin-ligase-rnf128-promotes-innate-antiviral-immunity-through-k63-linked-ubiquitination-of-tbk1
#8
Guanhua Song, Bingyu Liu, Zhihui Li, Haifeng Wu, Peng Wang, Kai Zhao, Guosheng Jiang, Lei Zhang, Chengjiang Gao
TBK1 is essential for interferon-β (IFN-β) production and innate antiviral immunity. Here we identified the T cell anergy-related E3 ubiquitin ligase RNF128 as a positive regulator of TBK1 activation. RNF128 directly interacted with TBK1 through its protease-associated (PA) domain and catalyzed the K63-linked polyubiquitination of TBK1, which led to TBK1 activation, IRF3 activation and IFN-β production. Deficiency of RNF128 expression attenuated IRF3 activation, IFN-β production and innate antiviral immune responses to RNA and DNA viruses, in vitro and in vivo...
December 2016: Nature Immunology
https://www.readbyqxmd.com/read/27764250/histone-h2b-ifi16-recognition-of-nuclear-herpesviral-genome-induces-cytoplasmic-interferon-%C3%AE-responses
#9
Jawed Iqbal, Mairaj Ahmed Ansari, Binod Kumar, Dipanjan Dutta, Arunava Roy, Leela Chikoti, Gina Pisano, Sujoy Dutta, Shahrooz Vahedi, Mohanan Valiya Veettil, Bala Chandran
IFI16 (gamma-interferon-inducible protein 16), a predominantly nuclear protein involved in transcriptional regulation, also functions as an innate immune response DNA sensor and induces the IL-1β and antiviral type-1 interferon-β (IFN-β) cytokines. We have shown that IFI16, in association with BRCA1, functions as a sequence independent nuclear sensor of episomal dsDNA genomes of KSHV, EBV and HSV-1. Recognition of these herpesvirus genomes resulted in IFI16 acetylation, BRCA1-IFI16-ASC-procaspase-1 inflammasome formation, cytoplasmic translocation, and IL-1β generation...
October 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27753621/rkip-and-tbk1-form-a-positive-feedback-loop-to-promote-type-i-interferon-production-in-innate%C3%A2-immunity
#10
Meidi Gu, Zhiyong Liu, Rongrong Lai, Si Liu, Wenlong Lin, Chuan Ouyang, Sheng Ye, He Huang, Xiaojian Wang
TANK-binding kinase 1 (TBK1) activation is a central event in type I interferon production in anti-virus innate immunity. However, the regulatory mechanism underlying TBK1 activation remains unclear. Here we report that Raf kinase inhibitory protein (RKIP) is essential for TBK1 activation and type I interferon production triggered by viral infection. Upon viral infection, RKIP is phosphorylated at serine 109 (S109) by TBK1. Phosphorylation of RKIP enhances its interaction with TBK1 and in turn promotes TBK1 autophosphorylation...
December 1, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27753515/tbk1-directs-wipi2-against-salmonella
#11
Keith B Boyle, Teresa L M Thurston, Felix Randow
Defense of the mammalian cell cytosol against Salmonella invasion is reliant upon capture of the infiltrating bacteria by macroautophagy (hereafter autophagy), a process controlled by the kinase TBK1. In our recent study we showed that recruitment of TBK1 activity to Salmonella stabilizes the key autophagy regulator WIPI2 on those bacteria, a novel and essential function for TBK1 in the control of the early steps of antibacterial autophagy. Substantial redundancy exists in the precise recruitment mechanism for TBK1 because engagement with any of several Salmonella-associated 'eat-me' signals, including host-derived glycans, and K48- and K63-linked ubiquitin chains, suffices to recruit TBK1 functionality...
October 18, 2016: Autophagy
https://www.readbyqxmd.com/read/27746698/in%C3%A2-vitro-and-in%C3%A2-vivo-anti-inflammatory-activities-of-korean-red-ginseng-derived-components
#12
Kwang-Soo Baek, Young-Su Yi, Young-Jin Son, Sulgi Yoo, Nak Yoon Sung, Yong Kim, Sungyoul Hong, Adithan Aravinthan, Jong-Hoon Kim, Jae Youl Cho
BACKGROUND: Although Korean Red Ginseng (KRG) has been traditionally used for a long time, its anti-inflammatory role and underlying molecular and cellular mechanisms have been poorly understood. In this study, the anti-inflammatory roles of KRG-derived components, namely, water extract (KRG-WE), saponin fraction (KRG-SF), and nonsaponin fraction (KRG-NSF), were investigated. METHODS: To check saponin levels in the test fractions, KRG-WE, KRG-NSF, and KRG-SF were analyzed using high-performance liquid chromatography...
October 2016: Journal of Ginseng Research
https://www.readbyqxmd.com/read/27743998/zebrafish-stat6-negatively-regulates-ifn%C3%AF-1-production-by-attenuating-the-kinase-activity-of-tank-binding-kinase-1
#13
Shun Li, Long-Feng Lu, Scott E LaPatra, Dan-Dan Chen, Yong-An Zhang
The aquatic spring viremia of carp virus (SVCV) causes significant mortality in common carp (Cyprinus carpio), and TBK1 plays a crucial role in the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) system by phosphorylating its substrates to induce type I interferons (IFNs) and cellular antiviral responses. In this study, we report that zebrafish STAT6 is induced during SVCV infection and reduces IFNφ1 expression by suppressing TBK1 phosphorylation. A typical IFN stimulatory response element (ISRE) motif was found in the promoter region of zebrafish STAT6, and zebrafish STAT6 transcription was significantly upregulated in the early stages of virus infection...
February 2017: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/27742471/yersinia-yopj-negatively-regulates-irf3-mediated-antibacterial-response-through-disruption-of-sting-mediated-cytosolic-dna-signaling
#14
Ye Cao, Kai Guan, Xiang He, Congwen Wei, Zirui Zheng, Yanhong Zhang, Shengli Ma, Hui Zhong, Wei Shi
The Yersinia outer protein J (YopJ) plays a pivotal role in evading the host immune response and establishes a persistent infection in host cells after bacterial infection. YopJ is a cysteine protease and can act as a deubiquitinating enzyme that deubiquitinates several targets in multiple signaling pathways. Stimulator of interferon genes (STING) is a critical adapter for the induction of interferon regulatory factor 3 (IRF3) phosphorylation and subsequent production of the cytokines in response to nucleic acids in the cytoplasm...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27721487/structural-and-functional-analysis-of-ddx41-a-bispecific-immune-receptor-for-dna-and-cyclic-dinucleotide
#15
Hiroki Omura, Daisuke Oikawa, Takanori Nakane, Megumi Kato, Ryohei Ishii, Ryuichiro Ishitani, Fuminori Tokunaga, Osamu Nureki
In the innate immune system, pattern recognition receptors (PRRs) specifically recognize ligands derived from bacteria or viruses, to trigger the responsible downstream pathways. DEAD box protein 41 (DDX41) is an intracellular PRR that triggers the downstream pathway involving the adapter STING, the kinase TBK1, and the transcription factor IRF3, to activate the type I interferon response. DDX41 is unique in that it recognizes two different ligands; i.e., double-stranded DNA (dsDNA) and cyclic dinucleotides (CDN), via its DEAD domain...
October 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27707838/activation-of-sting-dependent-innate-immune-signaling-by-s-phase-specific-dna-damage-in-breast-cancer
#16
Eileen E Parkes, Steven M Walker, Laura E Taggart, Nuala McCabe, Laura A Knight, Richard Wilkinson, Karen D McCloskey, Niamh E Buckley, Kienan I Savage, Manuel Salto-Tellez, Stephen McQuaid, Mary T Harte, Paul B Mullan, D Paul Harkin, Richard D Kennedy
BACKGROUND: Previously we identified a DNA damage response-deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. METHODS: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype...
January 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27705791/association-of-a-network-of-interferon-stimulated-genes-with-a-locus-encoding-a-negative-regulator-of-non-conventional-ikk-kinases-and-ifnb1
#17
Saloua Jeidane, Marie-Pier Scott-Boyer, Nicolas Tremblay, Sophie Cardin, Sylvie Picard, Martin Baril, Daniel Lamarre, Christian F Deschepper
Functional genomic analysis of gene expression in mice allowed us to identify a quantitative trait locus (QTL) linked in trans to the expression of 190 gene transcripts and in cis to the expression of only two genes, one of which was Ypel5. Most of the trans-expression QTL genes were interferon-stimulated genes (ISGs), and their expression in mouse macrophage cell lines was stimulated in an IFNB1-dependent manner by Ypel5 silencing. In human HEK293T cells, YPEL5 silencing enhanced the induction of IFNB1 by pattern recognition receptors and phosphorylation of TBK1/IKBKE kinases, whereas co-immunoprecipitation experiments revealed that YPEL5 interacted physically with IKBKE...
October 4, 2016: Cell Reports
https://www.readbyqxmd.com/read/27696330/dna-sensor-cgas-mediated-immune-recognition
#18
REVIEW
Pengyan Xia, Shuo Wang, Pu Gao, Guangxia Gao, Zusen Fan
The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types...
November 2016: Protein & Cell
https://www.readbyqxmd.com/read/27693916/inducible-costimulator-icos-potentiates-tcr-induced-calcium-flux-by-augmenting-plc%C3%AE-1-activation-and-actin-remodeling
#19
Julien Leconte, Sahar Bagherzadeh Yazdchi, Vincent Panneton, Woong-Kyung Suh
The inducible costimulator (ICOS) is a T cell costimulatory receptor that plays crucial roles in T cell differentiation and function. So far, ICOS has been shown to activate three signaling components: phosphoinositide 3-kinase (PI3K), intracellular calcium mobilization, and TANK binding kinase 1 (TBK1). By generating a knock-in strain of mice in which the ICOS gene is modified such that the ICOS-mediated PI3K pathway is selectively abrogated while the capacity of ICOS to mobilize intracellular calcium remains intact, we have shown that ICOS-mediated PI3K activation is required for some but not all T cell responses...
September 29, 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27693724/significance-of-optineurin-mutations-in-glaucoma-and-other-diseases
#20
REVIEW
Yuriko Minegishi, Mao Nakayama, Daisuke Iejima, Kazuhide Kawase, Takeshi Iwata
Glaucoma is one of the leading causes of bilateral blindness, affecting nearly 57 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells and is often associated with intraocular pressure (IOP). Normal tension glaucoma (NTG), marked by normal IOP but progressive glaucoma, is incompletely understood. In 2002, Sarfarazi et al. identified FIP-2 gene mutations responsible for hereditary NTG, renaming this gene "optineurin" (OPTN). Further investigations by multiple groups worldwide showed that OPTN is involved in several critical cellular functions, such as NF-κB regulation, autophagy, and vesicle transport...
November 2016: Progress in Retinal and Eye Research
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