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https://www.readbyqxmd.com/read/28325821/phosphorylation-of-the-exocyst-protein-exo84-by-tbk1-promotes-insulin-stimulated-glut4-trafficking
#1
Maeran Uhm, Merlijn Bazuine, Peng Zhao, Shian-Huey Chiang, Tingting Xiong, Sheelarani Karunanithi, Louise Chang, Alan R Saltiel
Insulin stimulates glucose uptake through the translocation of the glucose transporter GLUT4 to the plasma membrane. The exocyst complex tethers GLUT4-containing vesicles to the plasma membrane, a process that requires the binding of the G protein (heterotrimeric guanine nucleotide-binding protein) RalA to the exocyst complex. We report that upon activation of RalA, the protein kinase TBK1 phosphorylated the exocyst subunit Exo84. Knockdown of TBK1 blocked insulin-stimulated glucose uptake and GLUT4 translocation; knockout of TBK1 in adipocytes blocked insulin-stimulated glucose uptake; and ectopic overexpression of a kinase-inactive mutant of TBK1 reduced insulin-stimulated glucose uptake in 3T3-L1 adipocytes...
March 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/28325066/comprehensive-analysis-to-explain-reduced-or-increased-sod1-enzymatic-activity-in-als-patients-and-their-relatives
#2
Isil Keskin, Anna Birve, Mariusz Berdynski, Karin Hjertkvist, Reza Rofougaran, Torbjörn K Nilsson, Jonathan D Glass, Stefan L Marklund, Peter M Andersen
OBJECTIVE: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. METHODS: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed...
March 21, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28297677/recombinant-bcg-expressing-esx-1-of-mycobacterium-marinum-combines-low-virulence-with-cytosolic-immune-signaling-and-improved-tb-protection
#3
Matthias I Gröschel, Fadel Sayes, Sung Jae Shin, Wafa Frigui, Alexandre Pawlik, Mickael Orgeur, Robin Canetti, Nadine Honoré, Roxane Simeone, Tjip S van der Werf, Wilbert Bitter, Sang-Nae Cho, Laleh Majlessi, Roland Brosch
Recent insights into the mechanisms by which Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is recognized by cytosolic nucleotide sensors have opened new avenues for rational vaccine design. The only licensed anti-tuberculosis vaccine, Mycobacterium bovis BCG, provides limited protection. A feature of BCG is the partial deletion of the ESX-1 type VII secretion system, which governs phagosomal rupture and cytosolic pattern recognition, key intracellular phenotypes linked to increased immune signaling...
March 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28282485/contribution-of-mutations-in-known-mendelian-glaucoma-genes-to-advanced-early-onset-primary-open-angle-glaucoma
#4
Tiger Zhou, Emmanuelle Souzeau, Owen M Siggs, John Landers, Richard Mills, Ivan Goldberg, Paul R Healey, Stuart Graham, Alex W Hewitt, David A Mackey, Anna Galanopoulos, Robert J Casson, Jonathan B Ruddle, Jonathan Ellis, Paul Leo, Matthew A Brown, Stuart MacGregor, Shiwani Sharma, Kathryn P Burdon, Jamie E Craig
Purpose: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. Methods: The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing...
March 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28276468/nv-proteins-of-fish-novirhabdovirus-recruit-cellular-ppm1bb-protein-phosphatase-and-antagonize-rig-i-mediated-ifn-induction
#5
Stéphane Biacchesi, Emilie Mérour, Didier Chevret, Annie Lamoureux, Julie Bernard, Michel Brémont
Non virion (NV) protein expression is critical for fish Novirhabdovirus, viral hemorrhagic septicemia virus (VHSV) and infectious hematopoietic necrosis virus (IHNV), in vivo pathogenesis. However, the mechanism by which NV promotes the viral replication is still unclear. We developed an approach based on reverse genetics and interactomic and identified several NV-associated cellular partners underlying cellular pathways as potential viral targets. Among these cell partners, we showed that NV proteins specifically interact with a protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1Bb (PPM1Bb) and recruit it in the close vicinity of mitochondria, a subcellular compartment important for retinoic acid-inducible gene-I- (RIG-I)-mediated interferon induction pathway...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28275134/the-complement-anaphylatoxins-c5a-and-c3a-suppress-ifn-%C3%AE-production-in-response-to-listeria-monocytogenes-by-inhibition-of-the-cyclic-dinucleotide-activated-cytosolic-surveillance-pathway
#6
Stacey L Mueller-Ortiz, Daniel G Calame, Nancy Shenoi, Yi-Dong Li, Rick A Wetsel
Listeria monocytogenes is an intracellular Gram-positive bacterium that induces expression of type I IFNs (IFN-α/IFN-β) during infection. These cytokines are detrimental to the host during infection by priming leukocytes to undergo L. monocytogenes-mediated apoptosis. Our previous studies showed that C5aR1(-/-) and C3aR(-/-) mice are highly susceptible to L. monocytogenes infection as a result of increased IFN-β-mediated apoptosis of major leukocyte cell populations, including CD4(+) and CD8(+) T cells. However, the mechanisms by which C3a and C5a modulate IFN-β expression during L...
March 8, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28273337/ethanol-tlr3-and-tlr4-agonists-have-unique-innate-immune-responses-in-neuron-like-sh-sy5y-and-microglia-like-bv2
#7
Colleen J Lawrimore, Fulton T Crews
Ethanol (EtOH) consumption leads to an increase of proinflammatory signaling via activation of toll-like receptors (TLRs) such as TLR3 and TLR4 that leads to kinase activation (ERK1/2, p38, TBK1), transcription factor activation (NFκB, IRF3) and increased transcription of pro-inflammatory cytokines such as TNFα, IL-1β, and IL-6. This immune signaling cascade is thought to play a role in neurodegeneration and alcohol use disorders. While microglia are considered to be the primary macrophage in brain, it is unclear what if any role neurons play in ethanol-induced proinflammatory signaling METHODS: Microglia-like BV2 and retinoic acid differentiated neuron-like SH-SY5Y were treated with TLR3 agonist Poly(I:C), TLR4 agonist LPS, or EtOH for 10 or 30 minutes to examine proinflammatory immune signaling kinase and transcription factor activation using western blot, and for 24 hours to examine induction of proinflammatory gene mRNA using RT-PCR RESULTS: In BV2, both LPS and Poly(I:C) increased p-ERK1/2, p-p38, and p-NFκB by 30 minutes, whereas EtOH decreased p-ERK1/2 and increased p-IRF3...
March 8, 2017: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/28271436/the-tbk1-optn-axis-mediates-crosstalk-between-mitophagy-and-the-innate-immune-response-a-potential-therapeutic-target-for-neurodegenerative-diseases
#8
Lu He, Linxi Chen, Lanfang Li
No abstract text is available yet for this article.
March 7, 2017: Neuroscience Bulletin
https://www.readbyqxmd.com/read/28237848/il-17-axis-accelerates-the-inflammatory-progression-of-obese-in-mice-via-tbk1-and-ikbke-pathway
#9
Seung Hoon Lee, JooYeon Jhun, Jae-Kyung Byun, Eun-Kyung Kim, KyoungAh Jung, Ji Eun Lee, Jong Young Choi, Sung-Hwan Park, Mi-La Cho
Obesity mediates immune inflammatory response and induces IL-17 expression. Adipgenesis can be regulated by IL-17 and it causes TBK1 activation. The inhibition of TBK1 and the inhibition of I IKBKE reduces inflammatory response and improves obesity. It is hypothesized that IL-17 deficiency inhibits obesity progression and inflammation. 3T3-L1 preadipocytes were differentiated in vitro and treated with IL-17. RAW264.7 cells and differentiated 3T3-L1 were pretreated with TBK1 inhibitor and then stimulated with IL-17...
February 22, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28229125/the-clinical-neuroanatomical-and-neuropathologic-phenotype-of-tbk1-associated-frontotemporal-dementia-a-longitudinal-case-report
#10
Carolin A M Koriath, Martina Bocchetta, Emilie Brotherhood, Ione O C Woollacott, Penny Norsworthy, Javier Simón-Sánchez, Cornelis Blauwendraat, Katrina M Dick, Elizabeth Gordon, Sophie R Harding, Nick C Fox, Sebastian Crutch, Jason D Warren, Tamas Revesz, Tammaryn Lashley, Simon Mead, Jonathan D Rohrer
INTRODUCTION: Mutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD). However, the phenotype of TBK1-associated FTD is currently unclear. METHODS: We performed a single case longitudinal study of a patient who was subsequently found to have a novel A705fs mutation in the TBK1 gene. He was assessed annually over a 7-year period with a series of clinical, cognitive, and magnetic resonance imaging assessments...
2017: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
https://www.readbyqxmd.com/read/28188292/cytosolic-dna-promotes-signal-transducer-and-activator-of-transcription-3-stat3-phosphorylation-by-tank-binding-kinase-1-tbk1-to-restrain-stat3-activity
#11
Hung-Ching Hsia, Jessica E Hutti, Albert S Baldwin
Cytosolic DNA can elicit beneficial as well as undesirable immune responses. For example, viral or microbial DNA triggers cell-intrinsic immune responses to defend against infections, whereas aberrant cytosolic accumulation of self-DNA results in pathological conditions, such as autoimmunity. Given the importance of these DNA-provoked responses, a better understanding of their molecular mechanisms is needed. Cytosolic DNA engages stimulator of interferon genes (STING) to activate TANK-binding kinase 1 (TBK1), which subsequently phosphorylates the transcription factor interferon regulatory factor 3 (IRF3) to promote interferon expression...
February 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28159912/identification-of-tbk1-complexes-required-for-the-phosphorylation-of-irf3-and-the-production-of-interferon-b
#12
Siddharth Bakshi, Jordan Taylor, Sam Strickson, Thomas Macartney, Philip Cohen
The double-stranded RNA mimetic poly(I:C) and LPS activate Toll-like Receptor 3 (TLR3) and TLR4, respectively, triggering the activation of TANK-Binding Kinase 1 (TBK1) complexes, the phosphorylation of Interferon Regulatory Factor 3 (IRF3) and transcription of the Interferon b (IFNb) gene. Here, we demonstrate that the TANK-TBK1 and Optineurin (OPTN)-TBK1 complexes control this pathway. The poly(I:C)- or LPS-stimulated phosphorylation of IRF3 at Ser396 and production of IFNb were greatly reduced in bone-marrow-derived macrophages (BMDM) from TANK knock-out (KO) mice crossed to knock-in mice-expressing the ubiquitin-binding-defective OPTN[D477N] mutant...
February 3, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28150813/an-engineered-herpesvirus-activates-dendritic-cells-and-induces-protective-immunity
#13
Yijie Ma, Min Chen, Huali Jin, Bellur S Prabhakar, Tibor Valyi-Nagy, Bin He
Herpes simplex viruses (HSV) are human pathogens that switch between lytic and latent infection. While attenuated HSV is explored for vaccine, the underlying event remains poorly defined. Here we report that recombinant HSV-1 with a mutation in the γ134.5 protein, a virulence factor, stimulates dendritic cell (DC) maturation which is dependent on TANK-binding kinase 1 (TBK1). When exposed to CD11(+) DCs, the mutant virus that lacks the amino terminus of γ134.5 undergoes temporal replication without production of infectious virus...
February 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28148804/a-microrna-screen-identifies-the-wnt-signaling-pathway-as-a-regulator-of-the-interferon-response-during-flavivirus-infection
#14
Jessica L Smith, Sophia Jeng, Shannon K McWeeney, Alec J Hirsch
The impact of mosquito-borne flavivirus infections worldwide is significant, and many critical aspects of these viruses' biology, including virus-host interactions, host cell requirements for replication, and how virus-host interactions impact pathology, remain to be fully understood. The recent re-emergence and spread of flaviviruses, including dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV), highlights the importance of performing basic research on this important group of pathogens. MicroRNAs (miRNAs) are small, noncoding RNAs that modulate gene expression post-transcriptionally and have been demonstrated to regulate a broad range of cellular processes...
February 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28148298/tbk1-a-new-player-in-als-linking-autophagy-and-neuroinflammation
#15
REVIEW
James A Oakes, Maria C Davies, Mark O Collins
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder affecting motor neurons, resulting in progressive muscle weakness and death by respiratory failure. Protein and RNA aggregates are a hallmark of ALS pathology and are thought to contribute to ALS by impairing axonal transport. Mutations in several genes known to contribute to ALS result in deposition of their protein products as aggregates; these include TARDBP, C9ORF72, and SOD1. In motor neurons, this can disrupt transport of mitochondria to areas of metabolic need, resulting in damage to cells and can elicit a neuroinflammatory response leading to further neuronal damage...
February 2, 2017: Molecular Brain
https://www.readbyqxmd.com/read/28138020/the-type-ii-secretion-system-of-legionella-pneumophila-dampens-the-myd88-and-tlr2-signaling-pathway-in-infected-human-macrophages
#16
Celeste A Mallama, Kessler McCoy-Simandle, Nicholas P Cianciotto
Previously, we reported that mutants of L. pneumophila lacking a type II secretion (T2S) system elicit higher levels of cytokines (e.g., IL-6) following infection of U937 cells, a human macrophage-like cell line. We now show that this effect of T2S is also manifest upon infection of human THP-1 cell macrophages and peripheral blood monocytes but does not occur during infection of murine macrophages. Supporting the hypothesis that T2S acts to dampen the triggering of an innate immune response, we observed that the mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa-B (NF-κB) pathways are more highly stimulated upon infection with the T2S mutant compared to wild-type...
January 30, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28132838/human-cytomegalovirus-tegument-protein-ul82-inhibits-sting-mediated-signaling-to-evade-antiviral-immunity
#17
Yu-Zhi Fu, Shan Su, Yi-Qun Gao, Pei-Pei Wang, Zhe-Fu Huang, Ming-Ming Hu, Wei-Wei Luo, Shu Li, Min-Hua Luo, Yan-Yi Wang, Hong-Bing Shu
Recognition of human cytomegalovirus (HCMV) DNA by the cytosolic sensor cGAS initiates STING-dependent innate antiviral responses. HCMV can antagonize host immune responses to promote latency infection. However, it is unknown whether and how HCMV targets the cGAS-STING axis for immune evasion. Here we identified the HCMV tegument protein UL82 as a negative regulator of STING-dependent antiviral responses. UL82 interacted with STING and impaired STING-mediated signaling via two mechanisms. UL82 inhibited the translocation of STING from the ER to perinuclear microsomes by disrupting the STING-iRhom2-TRAPβ translocation complex...
February 8, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28125002/feline-panleucopenia-virus-ns2-suppresses-the-host-ifn-%C3%AE-induction-by-disrupting-the-interaction-between-tbk1-and-sting
#18
Hongtao Kang, Dafei Liu, Jin Tian, Xiaoliang Hu, Xiaozhan Zhang, Hang Yin, Hongxia Wu, Chunguo Liu, Dongchun Guo, Zhijie Li, Qian Jiang, Jiasen Liu, Liandong Qu
Feline panleucopenia virus (FPV) is a highly infectious pathogen that causes severe diseases in pets, economically important animals and wildlife in China. Although FPV was identified several years ago, little is known about how it overcomes the host innate immunity. In the present study, we demonstrated that infection with the FPV strain Philips-Roxane failed to activate the interferon β (IFN-β) pathway but could antagonize the induction of IFN stimulated by Sendai virus (SeV) in F81 cells. Subsequently, by screening FPV nonstructural and structural proteins, we found that only nonstructural protein 2 (NS2) significantly suppressed IFN expression...
January 23, 2017: Viruses
https://www.readbyqxmd.com/read/28123321/in%C3%A2-vitro-antioxidative-and-anti-inflammatory-effects-of-the-compound-k-rich-fraction-biogf1k-prepared-from-panax-ginseng
#19
Muhammad Jahangir Hossen, Yong Deog Hong, Kwang-Soo Baek, Sulgi Yoo, Yo Han Hong, Ji Hye Kim, Jeong-Oog Lee, Donghyun Kim, Junseong Park, Jae Youl Cho
BACKGROUND: BIOGF1K, a compound K-rich fraction prepared from the root of Panax ginseng, is widely used for cosmetic purposes in Korea. We investigated the functional mechanisms of the anti-inflammatory and antioxidative activities of BIOGF1K by discovering target enzymes through various molecular studies. METHODS: We explored the inhibitory mechanisms of BIOGF1K using lipopolysaccharide-mediated inflammatory responses, reporter gene assays involving overexpression of toll-like receptor adaptor molecules, and immunoblotting analysis...
January 2017: Journal of Ginseng Research
https://www.readbyqxmd.com/read/28119118/htlv-1-tax-impairs-k63-linked-ubiquitination-of-sting-to-evade-host-innate-immunity
#20
Jie Wang, Shuai Yang, Lu Liu, Hui Wang, Bo Yang
The cellular antiviral innate immune system is essential for host defense and viruses have evolved a variety of strategies to evade the innate immunity. Human T lymphotropic virus type 1 (HTLV-1) belongs to the deltaretrovirus family and it can establish persistent infection in human beings for many years. However, how this virus evades the host innate immune responses remains unclear. Here we report a new strategy used by HTLV-1 to block innate immune responses. We observed that stimulator of interferon genes (STING) limited HTLV-1 protein expression and was critical to HTLV-1 reverse transcription intermediate (RTI) ssDNA90 triggered interferon (IFN)-β production in phorbol12-myristate13-acetate (PMA)-differentiated THP1 (PMA-THP1) cells...
January 22, 2017: Virus Research
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