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https://www.readbyqxmd.com/read/29445009/human-binge-alcohol-intake-inhibits-tlr4-myd88-and-tlr4-trif-responses-but-not-the-tlr3-trif-pathway-hspa1a-and-pp1-play-selective-regulatory-roles
#1
Sujatha Muralidharan, Arlene Lim, Donna Catalano, Pranoti Mandrekar
Binge/moderate alcohol suppresses TLR4-MyD88 proinflammatory cytokines; however, alcohol's effects on TLR-TRIF signaling, especially after in vivo exposure in humans, are unclear. We performed a comparative analysis of the TLR4-MyD88, TLR4-TRIF, and TLR3-TRIF pathways in human monocytes following binge alcohol exposure. Mechanistic regulation of TLR-TRIF signaling by binge alcohol was evaluated by analyzing IRF3 and TBK1, upstream regulator protein phosphatase 1 (PP1), and immunoregulatory stress proteins HspA1A and XBP-1 in alcohol-treated human and mouse monocytes/macrophages...
February 14, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29444978/an-off-target-effect-of-bx795-blocks-herpes-simplex-virus-type-1-infection-of-the-eye
#2
Dinesh Jaishankar, Abraam M Yakoub, Tejabhiram Yadavalli, Alex Agelidis, Neel Thakkar, Satvik Hadigal, Joshua Ames, Deepak Shukla
Herpes simplex virus type 1 (HSV-1) causes recurrent mucocutaneous lesions in the eye that may advance to corneal blindness. Nucleoside analogs exemplified by acyclovir (ACV) form the primary class of antiherpetic drugs, but this class suffers limitations due to the emergence of viral resistance and other side effects. While studying the molecular basis of ocular HSV-1 infection, we observed that BX795, a commonly used inhibitor of TANK-binding kinase 1 (TBK1), strongly suppressed infection by multiple strains of HSV-1 in transformed and primary human cells, cultured human and animal corneas, and a murine model of ocular infection...
February 14, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29441066/tank-binding-kinase-1-tbk1-isoforms-negatively-regulate-type-i-interferon-induction-by-inhibiting-tbk1-irf3-interaction-and-irf3-phosphorylation
#3
Yi Wei Hu, Jie Zhang, Xiao Man Wu, Lu Cao, Pin Nie, Ming Xian Chang
TANK-binding kinase 1 (TBK1) is an important serine/threonine-protein kinase that mediates phosphorylation and nuclear translocation of IRF3, which contributes to induction of type I interferons (IFNs) in the innate antiviral response. In mammals, TBK1 spliced isoform negatively regulates the virus-triggered IFN-β signaling pathway by disrupting the interaction between retinoic acid-inducible gene I (RIG-I) and mitochondria antiviral-signaling protein (MAVS). However, it is still unclear whether alternative splicing patterns and the function of TBK1 isoform(s) exist in teleost fish...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29429998/zdhhc11-modulates-innate-immune-response-to-dna-virus-by-mediating-mita-irf3-association
#4
Ying Liu, Qian Zhou, Li Zhong, Heng Lin, Ming-Ming Hu, Yan Zhou, Hong-Bing Shu, Shu Li
MITA is a central adaptor in innate immune responses to DNA viruses. The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic. Here we identified ZDHHC11, a member of DHHC palmitoyl transferase family, as a positive regulator of DNA virus-triggered signaling. Overexpression of ZDHHC11 activated the IFN-β promoter, while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes. Zdhhc11-/- mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection...
February 12, 2018: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/29425491/tbk1-at-the-crossroads-of-inflammation-and-energy-homeostasis-in-adipose-tissue
#5
Peng Zhao, Kai In Wong, Xiaoli Sun, Shannon M Reilly, Maeran Uhm, Zhongji Liao, Yuliya Skorobogatko, Alan R Saltiel
The noncanonical IKK family member TANK-binding kinase 1 (TBK1) is activated by pro-inflammatory cytokines, but its role in controlling metabolism remains unclear. Here, we report that the kinase uniquely controls energy metabolism. Tbk1 expression is increased in adipocytes of HFD-fed mice. Adipocyte-specific TBK1 knockout (ATKO) attenuates HFD-induced obesity by increasing energy expenditure; further studies show that TBK1 directly inhibits AMPK to repress respiration and increase energy storage. Conversely, activation of AMPK under catabolic conditions can increase TBK1 activity through phosphorylation, mediated by AMPK's downstream target ULK1...
February 8, 2018: Cell
https://www.readbyqxmd.com/read/29421524/nontypeable-haemophilus-influenzae-dna-stimulates-type-i-interferon-expression-via-sting-signaling-pathway
#6
Chang Lu, Xuemei Zhang, Chenyu Ma, Wenchun Xu, Lingling Gan, Jin Cui, Yibing Yin, Hong Wang
Nontypeable Haemophilus influenzae (NTHI) is one of the leading causes of acute exacerbations of COPD (AECOPD). Although the immunoregulation function of NTHI outer member protein and endotoxin were confirmed, the role of NTHI DNA in activating immune responses remains to be elucidated. In this study, we found expression of IFN-β and IFN stimulated gene CXCL10 in host cells was forcefully elevated after treating with NTHI and NTHI DNA. Interestingly, we tested increased level of STING in NTHI infected mice lung...
February 5, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29398122/frequency-and-characteristics-of-the-tbk1-gene-variants-in-japanese-patients-with-sporadic-amyotrophic-lateral-sclerosis
#7
Genki Tohnai, Ryoichi Nakamura, Jun Sone, Masahiro Nakatochi, Daichi Yokoi, Masahisa Katsuno, Hazuki Watanabe, Hirohisa Watanabe, Mizuki Ito, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Masashi Aoki, Nobutaka Hattori, Osamu Onodera, Hiroya Naruse, Jun Mitsui, Yuji Takahashi, Jun Goto, Hiroyuki Ishiura, Shinichi Morishita, Jun Yoshimura, Koichiro Doi, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Naoki Atsuta, Gen Sobue
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1...
December 11, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29394115/structural-insights-into-the-ubiquitin-recognition-by-optn-optineurin-and-its-regulation-by-tbk1-mediated-phosphorylation
#8
Faxiang Li, Daichao Xu, Yingli Wang, Zixuan Zhou, Jianping Liu, Shichen Hu, Yukang Gong, Junying Yuan, Lifeng Pan
OPTN (optineurin), a ubiquitin-binding scaffold protein, functions as an important macroautophagy/autophagy receptor in selective autophagy processes. Mutations in OPTN have been linked with human neurodegenerative diseases including ALS and glaucoma. However, the mechanistic basis underlying the recognition of ubiquitin by OPTN and its regulation by TBK1-mediated phosphorylation are still elusive. Here, we demonstrate that the UBAN domain of OPTN preferentially recognizes linear ubiquitin chain and forms an asymmetric 2:1 stoichiometry complex with the linear diubiquitin...
February 2, 2018: Autophagy
https://www.readbyqxmd.com/read/29379028/an-evolutionary-ns1-mutation-enhances-zika-virus-evasion-of-host-interferon-induction
#9
Hongjie Xia, Huanle Luo, Chao Shan, Antonio E Muruato, Bruno T D Nunes, Daniele B A Medeiros, Jing Zou, Xuping Xie, Maria Isabel Giraldo, Pedro F C Vasconcelos, Scott C Weaver, Tian Wang, Ricardo Rajsbaum, Pei-Yong Shi
Virus-host interactions determine an infection outcome. The Asian lineage of Zika virus (ZIKV), responsible for the recent epidemics, has fixed a mutation in the NS1 gene after 2012 that enhances mosquito infection. Here we report that the same mutation confers NS1 to inhibit interferon-β induction. This mutation enables NS1 binding to TBK1 and reduces TBK1 phosphorylation. Engineering the mutation into a pre-epidemic ZIKV strain debilitates the virus for interferon-β induction; reversing the mutation in an epidemic ZIKV strain invigorates the virus for interferon-β induction; these mutational effects are lost in IRF3-knockout cells...
January 29, 2018: Nature Communications
https://www.readbyqxmd.com/read/29349657/association-between-tbk1-mutations-and-risk-of-amyotrophic-lateral-sclerosis-frontotemporal-dementia-spectrum-a-meta-analysis
#10
Rongrong Cui, Miao Tuo, Pengfei Li, Chang Zhou
Recently, mutations in TBK1 (TANK-binding kinase 1) have been reported to be a cause of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum, but the relationship between them remains unclear owing to the small sample size and low mutation rate. Therefore, we performed a two-stage meta-analysis to investigate the frequency of TBK1 mutations in ALS/FTD patients and the association between the mutations and risk of ALS/FTD spectrum. In the first stage, 12 studies involving 4173 ALS/FTD patients were included...
January 18, 2018: Neurological Sciences
https://www.readbyqxmd.com/read/29343779/characterization-of-signaling-pathways-regulating-the-expression-of-pro-inflammatory-long-form-thymic-stromal-lymphopoietin-upon-human-metapneumovirus-infection
#11
Youxian Li, Cecilie Lund, Ida Nervik, Simon Loevenich, Henrik Døllner, Marit W Anthonsen, Ingvild B Johnsen
Thymic stromal lymphopoietin (TSLP) is associated with several allergic diseases including asthma. Two isoforms of TSLP exist in humans, a long form (lfTSLP) and a short form (sfTSLP), displaying distinct immunological functions. Recently, TSLP was found to be upregulated in human airway cells upon human metapneumovirus (hMPV) infection, yet it remains unclear if the two isoforms are regulated differently during hMPV infection. Importantly, the molecular mechanisms underlying hMPV-mediated TSLP induction remain undescribed...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321042/type-i-ifn-signature-in-childhood-onset-systemic-lupus-erythematosus-a-conspiracy-of-dna-and-rna-sensing-receptors
#12
M Javad Wahadat, Iris L A Bodewes, Naomi I Maria, Cornelia G van Helden-Meeuwsen, Annette van Dijk-Hummelman, Eline C Steenwijk, Sylvia Kamphuis, Marjan A Versnel
BACKGROUND: Childhood-onset systemic lupus erythematosus (cSLE) is an incurable multi-systemic autoimmune disease. Interferon type I (IFN-I) plays a pivotal role in the pathogenesis of SLE. The objective of this study was to assess the prevalence of the IFN-I signature and the contribution of cytosolic nucleic acid receptors to IFN-I activation in a cohort of primarily white cSLE patients. METHODS: The IFN-I score (positive or negative), as a measure of IFN-I activation, was assessed using real-time quantitative PCR (RT-PCR) expression values of IFN-I signature genes (IFI44, IFI44L, IFIT1, Ly6e, MxA, IFITM1) in CD14+ monocytes of cSLE patients and healthy controls (HCs)...
January 10, 2018: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/29317664/human-cytomegalovirus-encoded-us9-targets-mavs-and-sting-signaling-to-evade-type-i-interferon-immune-responses
#13
Hyun Jin Choi, Areum Park, Sujin Kang, Eunhye Lee, Taeyun A Lee, Eun A Ra, Jiseon Lee, Sungwook Lee, Boyoun Park
Human cytomegalovirus (HCMV) has evolved sophisticated immune evasion mechanisms that target both the innate and adaptive immune responses. However, how HCMV encoded proteins are involved in this immune escape is not clear. Here, we show that HCMV glycoprotein US9 inhibits the IFN-β response by targeting the mitochondrial antiviral-signaling protein (MAVS) and stimulator of interferon genes (STING)-mediated signaling pathways. US9 accumulation in mitochondria attenuates the mitochondrial membrane potential, leading to promotion of MAVS leakage from the mitochondria...
January 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29315334/immune-related-genetic-enrichment-in-frontotemporal-dementia-an-analysis-of-genome-wide-association-studies
#14
Iris Broce, Celeste M Karch, Natalie Wen, Chun C Fan, Yunpeng Wang, Chin Hong Tan, Naomi Kouri, Owen A Ross, Günter U Höglinger, Ulrich Muller, John Hardy, Parastoo Momeni, Christopher P Hess, William P Dillon, Zachary A Miller, Luke W Bonham, Gil D Rabinovici, Howard J Rosen, Gerard D Schellenberg, Andre Franke, Tom H Karlsen, Jan H Veldink, Raffaele Ferrari, Jennifer S Yokoyama, Bruce L Miller, Ole A Andreassen, Anders M Dale, Rahul S Desikan, Leo P Sugrue
BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. METHODS AND FINDINGS: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis...
January 2018: PLoS Medicine
https://www.readbyqxmd.com/read/29279409/listeria-monocytogenes-triggers-noncanonical-autophagy-upon-phagocytosis-but-avoids-subsequent-growth-restricting-xenophagy
#15
Gabriel Mitchell, Mandy I Cheng, Chen Chen, Brittney N Nguyen, Aaron T Whiteley, Sara Kianian, Jeffery S Cox, Douglas R Green, Kent L McDonald, Daniel A Portnoy
Xenophagy is a selective macroautophagic process that protects the host cytosol by entrapping and delivering microbes to a degradative compartment. Both noncanonical autophagic pathways and xenophagy are activated by microbes during infection, but the relative importance and function of these distinct processes are not clear. In this study, we used bacterial and host mutants to dissect the contribution of autophagic processes responsible for bacterial growth restriction of Listeria monocytogenesL. monocytogenes is a facultative intracellular pathogen that escapes from phagosomes, grows in the host cytosol, and avoids autophagy by expressing three determinants of pathogenesis: two secreted phospholipases C (PLCs; PlcA and PlcB) and a surface protein (ActA)...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29251827/quantitative-proteomics-identified-ttc4-as-a-tbk1-interactor-and-a-positive-regulator-of-sev-induced-innate-immunity
#16
Jun Shang, Tian Xia, Qiang-Qiang Han, Xiaolu Zhao, Ming-Ming Hu, Hong-Bing Shu, Lin Guo
TBK1, STING and MDA5 are important players within the antiviral innate immune response network. We mapped the interactome of endogenous TBK1, STING and MDA5 by affinity enrichment mass spectrometry (AE-MS) in virally infected or uninfected THP-1 cells. Based on quantitative data of more than 2000 proteins and stringent statistical analysis, 58 proteins were identified as high-confidence interactors for at least one of three bait proteins. Our data indicated that TBK1 and MDA5 mostly interacted within preexisting protein networks, while STING interacted with different proteins with different viral infections...
December 18, 2017: Proteomics
https://www.readbyqxmd.com/read/29251796/lipotoxicity-induces-hepatic-protein-inclusions-through-tbk1-mediated-p62-sqstm1-phosphorylation
#17
Chun-Seok Cho, Hwan-Woo Park, Allison Ho, Ian A Semple, Boyoung Kim, Insook Jang, Haeli Park, Shannon Reilly, Alan R Saltiel, Jun Hee Lee
Obesity commonly leads to hepatic steatosis, which often provokes lipotoxic injuries to hepatocytes that cause non-alcoholic steatohepatitis (NASH). NASH in turn is associated with the accumulation of insoluble protein aggregates that are composed of ubiquitinated proteins and ubiquitin adaptor p62/sequestosome 1 (SQSTM1). The formation of p62 inclusions in hepatocytes is the critical marker that distinguishes simple fatty liver from NASH and predicts a poor prognostic outcome for subsequent liver carcinogenesis...
December 18, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29247853/cytosolic-sensing-of-immuno-stimulatory-dna-the-enemy-within
#18
REVIEW
Rekha Dhanwani, Mariko Takahashi, Sonia Sharma
In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2'-5'-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I)...
December 13, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29241030/expression-profiles-of-genes-involved-in-tlrs-and-nlrs-signaling-pathways-of-water-buffaloes-infected-with-fasciola-gigantica
#19
Fu-Kai Zhang, Jun-Ling Hou, Ai-Jiang Guo, Ai-Ling Tian, Zhao-An Sheng, Wen-Bin Zheng, Wei-Yi Huang, Hany M Elsheikha, Xing-Quan Zhu
Infection of ruminants and humans with Fasciola gigantica is attracting increasing attention due to its economic impact and public health significance. However, little is known of innate immune responses during F. gigantica infection. Here, we investigated the expression profiles of genes involved in Toll-like receptors (TLRs) and NOD-like receptors (NLRs) signaling pathways in buffaloes infected with 500F. gigantica metacercariae. Serum, liver and peripheral blood mononuclear cell (PBMC) samples were collected from infected and control buffaloes at 3, 10, 28, and 70days post infection (dpi)...
December 11, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/29222027/tbk1-from-orange-spotted-grouper-exerts-antiviral-activity-against-fish-viruses-and-regulates-interferon-response
#20
Yin Hu, Youhua Huang, Jiaxin Liu, Jingcheng Zhang, Qiwei Qin, Xiaohong Huang
TANK-binding kinase-1 (TBK1) has been well studied in mammals because of its importance in type I interferon induction in antiviral immunity. However, the roles of fish TBK1 in virus infection still remained largely uncertain. In the current study, a TBK1 homolog from orange-spotted grouper (Epinephelus coioides) (EcTBK1) was cloned and its roles in fish viral infections were investigated. Sequence analysis showed that EcTBK1 encoded a 723-amino acid peptide which shared 98% and 73% identity to large yellow croaker (Larimichthys crocea) and human (homo sapiens), respectively...
December 5, 2017: Fish & Shellfish Immunology
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