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https://www.readbyqxmd.com/read/29222027/tbk1-from-orange-spotted-grouper-exerts-antiviral-activity-against-fish-viruses-and-regulates-interferon-response
#1
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
https://www.readbyqxmd.com/read/29218456/assessment-of-tank-binding-kinase-1-as-a-therapeutic-target-in-cancer
#2
REVIEW
Victoria H Cruz, Rolf A Brekken
TANK-binding kinase 1 (TBK1) is central to multiple biological processes that promote tumorigenesis including cell division, autophagy, innate immune response and AKT-pro survival signaling. TBK1 is well studied and most known for its function in innate immunity. However, the serine threonine protein kinase received significant attention as a synthetic lethal partner and effector of the major oncogene, RAS. This review summarizes newly identified cancer promoting functions of TBK1 and evaluates the therapeutic potential of targeting TBK1 in cancer...
December 7, 2017: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/29215015/malaria-parasite-dna-harbouring-vesicles-activate-cytosolic-immune-sensors
#3
Xavier Sisquella, Yifat Ofir-Birin, Matthew A Pimentel, Lesley Cheng, Paula Abou Karam, Natália G Sampaio, Jocelyn Sietsma Penington, Dympna Connolly, Tal Giladi, Benjamin J Scicluna, Robyn A Sharples, Andreea Waltmann, Dror Avni, Eli Schwartz, Louis Schofield, Ziv Porat, Diana S Hansen, Anthony T Papenfuss, Emily M Eriksson, Motti Gerlic, Andrew F Hill, Andrew G Bowie, Neta Regev-Rudzki
STING is an innate immune cytosolic adaptor for DNA sensors that engage malaria parasite (Plasmodium falciparum) or other pathogen DNA. As P. falciparum infects red blood cells and not leukocytes, how parasite DNA reaches such host cytosolic DNA sensors in immune cells is unclear. Here we show that malaria parasites inside red blood cells can engage host cytosolic innate immune cell receptors from a distance by secreting extracellular vesicles (EV) containing parasitic small RNA and genomic DNA. Upon internalization of DNA-harboring EVs by human monocytes, P...
December 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/29212905/cyclic-gmp-amp-synthase-is-the-cytosolic-sensor-of-plasmodium-falciparum-genomic-dna-and-activates-type-i-ifn-in-malaria
#4
Carolina Gallego-Marin, Jacob E Schrum, Warrison A Andrade, Scott A Shaffer, Lina F Giraldo, Alvaro M Lasso, Evelyn A Kurt-Jones, Kate A Fitzgerald, Douglas T Golenbock
Innate immune receptors have a key role in the sensing of malaria and initiating immune responses. As a consequence of infection, systemic inflammation emerges and is directly related to signs and symptoms during acute disease. We have previously reported that plasmodial DNA is the primary driver of systemic inflammation in malaria, both within the phagolysosome and in the cytosol of effector cells. In this article, we demonstrate that Plasmodium falciparum genomic DNA delivered to the cytosol of human monocytes binds and activates cyclic GMP-AMP synthase (cGAS)...
December 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29180468/small-molecule-inhibition-of-axl-targets-tumor-immune-suppression-and-enhances-chemotherapy-in-pancreatic-cancer
#5
Kathleen F Ludwig, Wenting Du, Noah Sorrelle, Katarzyna Wnuk-Lipinska, Mary Topalovski, Jason E Toombs, Victoria H Cruz, Shinichi Yabuuchi, N V Rajeshkumar, Anirban Maitra, James B Lorens, Rolf A Brekken
Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDA), where it coordinately mediates immune evasion and drug resistance. Here we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor-immune interface to blunt the aggressive traits of PDA cells in vitro and enhance gemcitibine efficacy in vivo. Axl signaling stimulates the TBK1-NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response and an immune stimulatory microenvironment...
November 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29177862/measuring-innate-immune-responses-to-bacterial-viability
#6
Julien Moretti, Nicolas Vabret, J Magarian Blander
The innate immune system directly senses microbial viability via the detection of a special class of viability-associated pathogen-associated molecular patterns (vita-PAMPs), such as prokaryotic messenger RNA. In the case of Gram-negative bacteria, detection of bacterial viability by phagocytes leads to a unique activation of inflammasome and type I interferon pathways, resulting in a robust pro-inflammatory innate response and a vigorous adaptive immune response. This protocol describes the methods required to study activation of both inflammasome and type I interferon pathways after stimulation of mouse bone marrow-derived macrophages with live or killed Gram-negative and Gram-positive bacteria...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29161701/yin-yang-1-dynamically-regulates-antiviral-innate-immune-responses-during-viral-infection
#7
Jie Zan, Hao Zhang, Ai-Ping Gu, Kai-Lun Zhong, Min-Yi Lu, Xiao-Xin Bai, Jin-Yang Zhang, Jun Cai
BACKGROUND/AIMS: Type I interferon (IFN-1) production and IFN-1 signaling play critical roles in the host antiviral innate immune responses. Although transcription factor Yin Yang 1 (YY1) has been reported to have a dual activator/repressor role during the regulation of interferon beta (IFN-β) promoter activity, the roles of YY1 in the regulation of upstream signaling pathways leading to IFN-1 induction and IFN-1 signaling during viral infection remain to be elucidated. METHODS: The roles of YY1 in IFN-1 production and IFN-1 signaling were investigated using immunoblotting, real-time PCR, small interfering RNA (siRNA)-mediated YY1 knockdown, YY1 overexpression by transient transfection, and co-immunoprecipitation, using mouse cells...
November 20, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29155197/dyrk2-mediated-the-release-of-proinflammatory-cytokines-in-lps-induced-bv2-cells
#8
Li Xu, Yuxiang Sun, Mengmeng Li, Xin Ge
NF-κB pathway and p38MAPK (p38mitogen-activated protein kinase) pathway have been shown to play a key role in neuroinflammation, however, the phosphorylation modification is an important process that affects the activation of above pathways. Dual-specificity tyrosine-phosphorylation-regulated kinase 2(Dyrk2), as a phosphokinase that can phosphorylate signal molecules, has been demonstrated to regulate Type I Interferon(TIF) by promoting ser527 phosphorylation of TBK1. Therefore, to investigate the role of Dyrk2 in neuroinflammation, we analyzed the effect of Dyrk2 on LPS-induced the activation of microglia...
November 16, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29154141/novel-genes-associated-with-amyotrophic-lateral-sclerosis-diagnostic-and-clinical-implications
#9
REVIEW
Ruth Chia, Adriano Chiò, Bryan J Traynor
BACKGROUND: The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research aims to understand the underlying mechanisms of ALS and identify potential therapeutic targets. The first gene associated with ALS was SOD1, identified in 1993 and, by early 2014, more than 20 genes had been identified as causative of, or highly associated with, ALS. These genetic discoveries have identified key disease pathways that are therapeutically testable and could potentially lead to the development of better treatments for people with ALS...
November 16, 2017: Lancet Neurology
https://www.readbyqxmd.com/read/29150432/the-ikk-related-kinase-tbk1-activates-mtorc1-directly-in-response-to-growth-factors-and-innate-immune-agonists
#10
Cagri Bodur, Dubek Kazyken, Kezhen Huang, Bilgen Ekim Ustunel, Kate A Siroky, Aaron Seth Tooley, Ian E Gonzalez, Daniel H Foley, Hugo A Acosta-Jaquez, Tammy M Barnes, Gabrielle K Steinl, Kae-Won Cho, Carey N Lumeng, Steven M Riddle, Martin G Myers, Diane C Fingar
The innate immune kinase TBK1 initiates inflammatory responses to combat infectious pathogens by driving production of type I interferons. TBK1 also controls metabolic processes and promotes oncogene-induced cell proliferation and survival. Here, we demonstrate that TBK1 activates mTOR complex 1 (mTORC1) directly. In cultured cells, TBK1 associates with and activates mTORC1 through site-specific mTOR phosphorylation (on S2159) in response to certain growth factor receptors (i.e., EGF-receptor but not insulin receptor) and pathogen recognition receptors (PRRs) (i...
November 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29149916/whole-exome-sequencing-in-amyotrophic-lateral-sclerosis-suggests-nek1-is-a-risk-gene-in-chinese
#11
Jacob Gratten, Qiongyi Zhao, Beben Benyamin, Fleur Garton, Ji He, Paul J Leo, Marie Mangelsdorf, Lisa Anderson, Zong-Hong Zhang, Lu Chen, Xiang-Ding Chen, Katie Cremin, Hong-Weng Deng, Janette Edson, Ying-Ying Han, Jessica Harris, Anjali K Henders, Zi-Bing Jin, Zhongshan Li, Yong Lin, Xiaolu Liu, Mhairi Marshall, Bryan J Mowry, Shu Ran, David C Reutens, Sharon Song, Li-Jun Tan, Lu Tang, Robyn H Wallace, Lawrie Wheeler, Jinyu Wu, Jian Yang, Huji Xu, Peter M Visscher, Perry F Bartlett, Matthew A Brown, Naomi R Wray, Dongsheng Fan
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry...
November 17, 2017: Genome Medicine
https://www.readbyqxmd.com/read/29146049/common-and-rare-tbk1-variants-in-early-onset-alzheimer-disease-in-a-european-cohort
#12
Jan Verheijen, Julie van der Zee, Ilse Gijselinck, Tobi Van den Bossche, Lubina Dillen, Bavo Heeman, Estrella Gómez-Tortosa, Albert Lladó, Raquel Sanchez-Valle, Caroline Graff, Pau Pastor, Maria A Pastor, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Jordi Clarimon, Alexandre de Mendonça, Ellen Gelpi, Magda Tsolaki, Janine Diehl-Schmid, Benedetta Nacmias, Maria Rosário Almeida, Barbara Borroni, Radoslav Matej, Agustín Ruiz, Sebastiaan Engelborghs, Rik Vandenberghe, Peter P De Deyn, Marc Cruts, Christine Van Broeckhoven, Kristel Sleegers
TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls...
October 25, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29138248/usp1-uaf1-deubiquitinase-complex-stabilizes-tbk1-and-enhances-antiviral-responses
#13
Zhongxia Yu, Hui Song, Mutian Jia, Jintao Zhang, Wenwen Wang, Qi Li, Lining Zhang, Wei Zhao
Optimal activation of TANK-binding kinase 1 (TBK1) is crucial for initiation of innate antiviral immunity and maintenance of immune homeostasis. Although several E3 ubiquitin ligases have been reported to regulate TBK1 activation by mediating its polyubiquitination, the functions of deubiquitinase on TBK1 activity remain largely unclear. Here, we identified a deubiquitinase complex, which is formed by ubiquitin specific peptidase 1 (USP1) and USP1-associated factor 1 (UAF1), as a viral infection-induced physiological enhancer of TBK1 expression...
November 14, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29137817/beyond-als-and-ftd-the-phenotypic-spectrum-of-tbk1-mutations-includes-psp-like-and-cerebellar-phenotypes
#14
Carlo Wilke, Jonathan Baets, Jan L De Bleecker, Tine Deconinck, Saskia Biskup, Stefanie N Hayer, Stephan Züchner, Rebecca Schüle, Peter De Jonghe, Matthis Synofzik
Mutations in the TANK-binding kinase 1 gene (TBK1) are a rare, but recurrent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the complete phenotypic spectrum of syndromes associated with TBK1 mutations remains to be elucidated. Using next-generation panel-sequencing of neurodegenerative disease genes, we identified a TBK1 index patient presenting with a progressive supranuclear palsy-like syndrome. Consecutively, we screened the whole-exome sequencing data of 439 index subjects presenting with various neurodegenerative syndromes outside the ALS-FTD spectrum for TBK1 mutations...
October 24, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29133417/human-resistin-protects-against-endotoxic-shock-by-blocking-lps-tlr4-interaction
#15
Jessica C Jang, Jiang Li, Luca Gambini, Hashini M Batugedara, Sandeep Sati, Mitchell A Lazar, Li Fan, Maurizio Pellecchia, Meera G Nair
Helminths trigger multiple immunomodulatory pathways that can protect from sepsis. Human resistin (hRetn) is an immune cell-derived protein that is highly elevated in helminth infection and sepsis. However, the function of hRetn in sepsis, or whether hRetn influences helminth protection against sepsis, is unknown. Employing hRetn-expressing transgenic mice (hRETNTg+) and recombinant hRetn, we identify a therapeutic function for hRetn in lipopolysaccharide (LPS)-induced septic shock. hRetn promoted helminth-induced immunomodulation, with increased survival of Nippostrongylus brasiliensis (Nb)-infected hRETNTg+ mice after a fatal LPS dose compared with naive mice or Nb-infected hRETNTg- mice...
November 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29125880/mavs-activates-tbk1-and-ikk%C3%AE%C2%B5-through-trafs-in-nemo-dependent-and-independent-manner
#16
Run Fang, Qifei Jiang, Xiang Zhou, Chenguang Wang, Yukun Guan, Jianli Tao, Jianzhong Xi, Ji-Ming Feng, Zhengfan Jiang
Mitochondrial antiviral-signaling protein (MAVS) transmits signals from RIG-I-like receptors after RNA virus infections. However, the mechanism by which MAVS activates downstream components, such as TBK1 and IKKα/β, is unclear, although previous work suggests the involvement of NEMO or TBK1-binding proteins TANK, NAP1, and SINTBAD. Here, we report that MAVS-mediated innate immune activation is dependent on TRAFs, partially on NEMO, but not on TBK1-binding proteins. MAVS recruited TBK1/IKKε by TRAFs that were pre-associated with TBK1/IKKε via direct interaction between the coiled-coil domain of TRAFs and the SDD domain of TBK1/IKKε...
November 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29106411/extrachromosomal-telomere-repeat-dna-is-linked-to-alt-development-via-cgas-sting-dna-sensing-pathway
#17
Yi-An Chen, Yi-Ling Shen, Hsuan-Yu Hsia, Yee-Peng Tiang, Tzu-Ling Sung, Liuh-Yow Chen
Extrachromosomal telomere repeat (ECTR) DNA is unique to cancer cells that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, but the role of ECTRs in ALT development remains elusive. We found that induction of ECTRs in normal human fibroblasts activated the cGAS-STING-TBK1-IRF3 signaling axis to trigger IFNβ production and a type I interferon response, resulting in cell-proliferation defects. In contrast, ALT cancer cells are commonly defective in sensing cytosolic DNA. We found that STING expression was inhibited in ALT cancer cell lines and transformed ALT cells...
November 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29103041/association-of-the-new-variant-tyr424asp-at-tbk1-gene-with-amyotrophic-lateral-sclerosis-and-cognitive-decline
#18
Irene Piaceri, Valentina Bessi, Sabrina Matà, Cristina Polito, Andrea Tedde, Valentina Berti, Silvia Bagnoli, Arianna Braccia, Monica Del Mastio, Alberto Moggi Pignone, Alberto Pupi, Sandro Sorbi, Benedetta Nacmias
A new risk gene associated with amyotrophic lateral sclerosis (ALS) has recently been identified: the Tank-binding kinase 1 (TBK1) gene. Up to now, 90 TBK1 variants have been described in ALS patients with or without frontotemporal dementia (FTD), thus making TBK1 the third or fourth most frequent genetic cause of ALS and FTD. A point mutation analysis in a cohort of 69 Italian ALS patients was performed in order to analyze the frequency of TBK1 mutations and the correlation with clinical phenotypes. The analysis identified the novel variant p...
October 30, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29101162/ex-vivo-profiling-of-pd-1-blockade-using-organotypic-tumor-spheroids
#19
Russell W Jenkins, Amir R Aref, Patrick H Lizotte, Elena Ivanova, Susanna Stinson, Chensheng W Zhou, Michaela Bowden, Jiehui Deng, Hongye Liu, Diana Miao, Meng Xiao He, William Walker, Gao Zhang, Tian Tian, Chaoran Cheng, Zhi Wei, Sangeetha Palakurthi, Mark Bittinger, Hans Vitzthum, Jong Wook Kim, Ashley Merlino, Max Quinn, Chandrasekar Venkataramani, Joshua A Kaplan, Andrew Portell, Prafulla C Gokhale, Bart Phillips, Alicia Smart, Asaf Rotem, Robert E Jones, Lauren Keogh, Maria Anguiano, Lance Stapleton, Zhiheng Jia, Michal Barzily-Rokni, Israel Cañadas, Tran C Thai, Marc R Hammond, Raven Vlahos, Eric S Wang, Hua Zhang, Shuai Li, Glenn J Hanna, Wei Huang, Mai P Hoang, Adriano Piris, Jean-Pierre Eliane, Anat O Stemmer-Rachamimov, Lisa Cameron, Mei-Ju Su, Parin Shah, Benjamin Izar, Manisha Thakuria, Nicole R LeBoeuf, Guilherme Rabinowits, Viswanath Gunda, Sareh Parangi, James M Cleary, Brian C Miller, Shunsuke Kitajima, Rohit Thummalapalli, Benchun Miao, Thanh U Barbie, Vivek Sivathanu, Joshua Wong, William G Richards, Raphael Bueno, Charles H Yoon, Juan Miret, Meenhard Herlyn, Levi A Garraway, Eliezer M Van Allen, Gordon J Freeman, Paul T Kirschmeier, Jochen H Lorch, Patrick A Ott, F Stephen Hodi, Keith T Flaherty, Roger D Kamm, Genevieve M Boland, Kwok-Kin Wong, David Dornan, Cloud Peter Paweletz, David A Barbie
Ex vivo systems that incorporate features of the tumor microenvironment (TME) and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations, and respond to ICB in short-term 3-dimensional microfluidic culture...
November 3, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29046251/mycobacterium-tuberculosis-esat6-induces-ifn-%C3%AE-gene-expression-in-macrophages-via-tlrs-mediated-signaling
#20
Ah-Ra Jang, Joo-Hee Choi, Sung Jae Shin, Jong-Hwan Park
Mycobacterium tuberculosis is a highly virulent bacterium that causes tuberculosis. It infects about one third of the world's population. Type I interferons (IFNs) play a detrimental role in host defense against M. tuberculosis infection. Proteins secreted by M. tuberculosis through ESX-1 secretion system contribute to type I IFNs production. However, the precise mechanism by which 6-kDa early secretory antigen target (ESAT6), one of ESX-1-mediated secretory proteins, induces type I IFNs production in host cells is currently unclear...
October 15, 2017: Cytokine
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