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https://www.readbyqxmd.com/read/28428627/glucocorticoids-suppress-antimicrobial-autophagy-and-nitric-oxide-production-and-facilitate-mycobacterial-survival-in-macrophages
#1
Jinli Wang, Ruining Wang, Hui Wang, Xiaofan Yang, Jiahui Yang, Wenjing Xiong, Qian Wen, Li Ma
Chronic administration of glucocorticoids has been shown to render individuals highly susceptible to mycobacterial infection and lead to reactivation of latent bacilli. However, the effect of glucocorticoids on innate anti-mycobacterial defense, especially in macrophages remains largely unknown. Here, we found that glucocorticoids inhibited the innate immune response, antimicrobial nitric oxide production and autophagy in mycobacteria-challenged macrophages. Meanwhile, maturation and acidification of mycobacterial phagosomes were attenuated in RAW264...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28426911/tbk1-ikke-blockade-inhibits-mutant-sting-mediated-inflammatory-response-in-patient-cells
#2
Marie-Louise Frémond, Carolina Uggenti, Lien Van Eyck, Isabelle Melki, Vincent Bondet, Naoki Kitabayashi, Christina Hertel, Adrian Hayday, Bénédicte Neven, Yoann Rose, Darragh Duffy, Yanick J Crow, Mathieu P Rodero
OBJECTIVE: Gain-of-function mutations in TMEM173 encoding STING (stimulator of interferon genes) underlie a novel type I interferonopathy, minimally responsive to conventional immunosuppressive therapies and associated with high childhood morbidity and mortality. STING gain-of-function causes constitutive over secretion of interferon (IFN). We determined the effects of a TBK1/IKKE inhibitor (BX795) on IFN secretion and signaling in primary peripheral blood mononuclear cells (PBMCs) from four patients...
April 20, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28425986/p16ink4a-upregulation-mediated-by-tbk1-induces-retinal-ganglion-cell-senescence-in-ischemic-injury
#3
L U Li, Yin Zhao, Hong Zhang
Glaucoma is a leading cause of irreversible blindness worldwide that is characterized by progressive retinal ganglion cell (RGC) death. However, RGC senescence as a phase before RGC death, and the mechanism of RGC senescence remains unclear. Here, we demonstrate that TANK-binding protein 1 (TBK1) is upregulated in acute IOP elevation-induced ischemic retinas mouse model. Moreover, pre-treatment with the TBK1 inhibitor BX-795 reduced p16INK4a (p16) expression and RGC senescence. Upregulation of TBK1 via plasmid transfection increased Akt phosphorylation at Ser473 and Bmi1 phosphorylation...
April 20, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28423339/germ-cell-specific-inflammasome-component-nlrp14-negatively-regulates-cytosolic-nucleic-acid-sensing-to-promote-fertilization
#4
Takayuki Abe, Albert Lee, Ramaswami Sitharam, Jordan Kesner, Raul Rabadan, Sagi D Shapira
Cytosolic sensing of nucleic acids initiates tightly regulated programs to limit infection. Oocyte fertilization represents a scenario wherein inappropriate responses to exogenous yet non-pathogen-derived nucleic acids would have negative consequences. We hypothesized that germ cells express negative regulators of nucleic acid sensing (NAS) in steady state and applied an integrated data-mining and functional genomics approach to identify a rheostat of DNA and RNA sensing-the inflammasome component NLRP14. We demonstrated that NLRP14 interacted physically with the nucleic acid sensing pathway and targeted TBK1 (TANK binding kinase 1) for ubiquitination and degradation...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28422568/cgas-sting-tbk1-irf3-7-induced-interferon-%C3%AE-contributes-to-the-clearing-of-non-tuberculous-mycobacterial-infection-in-mice
#5
Nanthapon Ruangkiattikul, Andreas Nerlich, Ketema Abdissa, Stefan Lienenklaus, Abdulhadi Suwandi, Nina Janze, Kristin Laarmann, Julia Spanier, Ulrich Kalinke, Siegfried Weiss, Ralph Goethe
Type I interferons (IFN-I), such as IFN-α and IFN-β are important messengers in the host response against bacterial infections. Knowledge about the role of IFN-I in infections by nontuberculous mycobacteria (NTM) is limited. Here we show that macrophages infected with pathogens of the Mycobacterium avium complex produced significantly lower amounts of IFN-β than macrophages infected with the opportunistic pathogen M. smegmatis. To dissect the molecular mechanisms of this phenomenon, we focussed on the obligate pathogen Mycobacterium avium ssp...
April 19, 2017: Virulence
https://www.readbyqxmd.com/read/28415024/glucocorticoids-differentially-regulate-the-innate-immune-responses-of-tlr4-and-the-cytosolic-dna-sensing-pathway
#6
Jinli Wang, Ruining Wang, Jiahui Yang, Xiaofan Yang, Shengfeng Hu, Hui Wang, Chaoying Zhou, Wenjing Xiong, Qian Wen, Li Ma
Glucocorticoids (GCs) are widely used to treat the chronic inflammatory disorders because of their powerful anti-inflammatory properties; however, their effects on macrophage-mediated immune responses are not completely understood. In the present study, we found that GCs decreased LPS-mediated TBK1 activation and the expression of IFN-β, RANTES and CXCL-10; however, poly(dA:dT)-induced TBK1 activity and cytokine expression were not affected by GCs treatment. Furthermore, GCs decreased the expression of key autophagy-related genes (ATGs), including ATG5, ATG7 and ATG12, and inhibited autophagy in macrophages after LPS stimulation...
April 14, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28414768/gpatch3-negatively-regulates-rlr-mediated-innate-antiviral-responses-by-disrupting-the-assembly-of-visa-signalosome
#7
Ying Nie, Yong Ran, Hong-Yan Zhang, Zhe-Fu Huang, Zhao-Yi Pan, Su-Yun Wang, Yan-Yi Wang
Upon viral infection, retinoic acid-inducible gene I-like receptors (RLRs) recognize viral RNA and trigger a series of signaling events, leading to the induction of type I interferons (IFNs). These processes are delicately regulated to prevent excessive and harmful immune responses. In this study, we identified G patch domain-containing protein 3 (GPATCH3) as a negative regulator of RLR-mediated antiviral signaling pathways. Overexpression of GPATCH3 impaired RNA virus- triggered induction of downstream antiviral genes, whereas its knockdown had opposite effects and attenuated viral replication...
April 17, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28412547/intracellular-dna-sensing-pathway-of-cgas-cgamp-is-decreased-in-human-newborns-and-young-children
#8
Zhan-Sheng Wang, Yu-Lu Liu, Nan Mi, Dao-Yun Duan
Newborns are highly susceptible to DNA virus infections, which may result from the characteristics of neonatal innate immune systems. Here we analyzed for the first time the development of innate immune sensing and signaling of intracellular DNA virus infection in human newborns and young children. Both mRNA and protein expression of cGAS, an intracellular DNA sensor, were shown to be significantly reduced in neonatal peripheral blood mononuclear cells (PBMCs). In addition, cGAS expression in neonatal PBMCs could be induced upon herpes simplex virus type 1 (HSV-1) or interferon-α (IFNα) stimulation...
April 13, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28411188/raf-kinase-inhibitor-protein-preferentially-promotes-tlr3-triggered-signaling-and-inflammation
#9
Rongrong Lai, Meidi Gu, Wei Jiang, Wenlong Lin, Penglei Xu, Zhiyong Liu, He Huang, Huazhang An, Xiaojian Wang
Raf kinase inhibitor protein (RKIP) protects against host immunological responses in nematodes and Drosophila Whether RKIP functions in innate immune responses in mammals remains unknown. In this article, we report that RKIP preferentially regulates the TLR3-mediated immune response in macrophages. RKIP deficiency or silencing significantly decreases polyinosinic:polycytidylic acid [Poly(I:C)]-induced IFN-β, IL-6, and TNF-α production without affecting the counterpart induced by LPS or CpG. Compared with their wild-type counterparts, RKIP-deficient mice produce less IFN-β, IL-6, and TNF-α in serum and display decreased lethality upon peritoneal Poly(I:C) plus d-galactosamine injection...
April 14, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28407409/clinical-and-molecular-characterization-of-a-second-family-with-the-12q14-microdeletion-syndrome-and-review-of-the-literature
#10
Rita Fischetto, Orazio Palumbo, Federica Ortolani, Pietro Palumbo, Maria Pia Leone, Francesco Andrea Causio, Sabino Pesce, Maria Christina Digilio, Massimo Carella, Francesco Papadia
The 12q14 microdeletion syndrome is a rare condition characterized by low birth weight, failure to thrive, short stature, learning disabilities, and osteopoikilosis. To date, 20 cases of 12q14 deletion have been reported in the literature, displaying both phenotypic than genetic variability. We report on three familial cases, a mother and two brothers, with severe short stature. The mother and elder brother presented with osteopoikilosis while the younger brother had severe short stature and developmental delay...
April 13, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28402257/-dead-box-rna-helicase-3-modulates-nf-%C3%AE%C2%BAb-signal-pathway-by-controlling-the-phosphorylation-of-pp2a-c-subunit
#11
Xin Wang, Rui Wang, Miao Luo, Chen Li, Hua-Xia Wang, Chang-Chao Huan, Yu-Rong Qu, Ying Liao, Xiang Mao
Asp-Glu-Ala-Asp (DEAD)-box RNA helicase 3 (DDX3), an ATP-dependent RNA helicase, is associated with RNA splicing, mRNA export, transcription, translation, and RNA decay. Recent studies revealed that DDX3 participates in innate immune response during virus infection by interacting with TBK1 and regulating the production of IFN-β. In our studies, we demonstrated that DDX3 regulated NF-κB signal pathway. We found that DDX3 knockdown reduced the phosphorylation of p65 and IKK-β and ultimately attenuated the production of inflammatory cytokines induced by poly(I:C) or TNF-α stimulation...
March 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28399655/cyclic-gmp-amp-as-an-endogenous-second-messenger-in-innate-immune-signaling-by-cytosolic-dna
#12
Kazuki Kato, Hiroki Omura, Ryuichiro Ishitani, Osamu Nureki
The innate immune system functions as the first line of defense against invading bacteria and viruses. In this context, the cGAS/STING [cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase/ STING] signaling axis perceives the nonself DNA associated with bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. In this pathway, the noncanonical cyclic dinucleotide 2',3'-cyclicGMP-AMP(2',3'-cGAMP) functions as a second messenger for signal transduction: 2',3'-cGAMP is produced by the enzyme cGAS upon its recognition of double-stranded DNA, and then the 2',3'-cGAMP is recognized by the receptor STING to induce the phosphorylation of downstream factors, including TBK1 (TANK binding kinase 1) and IRF3 (interferon regulatory factor 3)...
April 7, 2017: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/28396343/cyclic-dinucleotides-modulate-induced-type-i-ifn-responses-in-innate-immune-cells-by-degradation-of-sting
#13
Christine Rueckert, Ulfert Rand, Urmi Roy, Bahram Kasmapour, Till Strowig, Carlos A Guzmán
The cyclic dinucleotides, GMP-AMP (cGAMP) and c-di-AMP [bis-(3',5')-cyclic dimeric AMP], are potent type I IFN inducers via STING-TBK1-IRF3 cascade. They are promising adjuvants that promote antigen-specific humoral and cellular immune responses in different preclinical models; however, an optimal outcome of vaccination depends on a balanced immune activation. Here, we characterize the process of IFN-β induction by c-di-AMP and cGAMP in an in vitro model on the basis of primary mouse dendritic cells. Results obtained show decreased IFN-β production upon prolonged cell stimulation...
April 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28392570/human-t-cell-lymphotropic-virus-type-1-and-its-oncogenesis
#14
REVIEW
Lan-Lan Zhang, Jing-Yun Wei, Long Wang, Shi-le Huang, Ji-Long Chen
Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL), a rapidly progressing clonal malignancy of CD4+ T lymphocytes. Exploring the host-HTLV-1 interactions and the molecular mechanisms underlying HTLV-1-mediated tumorigenesis is critical for developing efficient therapies against the viral infection and associated leukemia/lymphoma. It has been demonstrated to date that several HTLV-1 proteins play key roles in the cellular transformation and immortalization of infected T lymphocytes...
April 10, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28380318/recent-advances-in-the-molecular-genetics-of-frontotemporal-lobar-degeneration
#15
REVIEW
Innocenzo Rainero, E Rubino, A Michelerio, F D'Agata, Salvatore Gentile, Lorenzo Pinessi
The term frontotemporal lobar degeneration (FTLD) describes a spectrum of neurodegenerative disorders associated with deposition of misfolded proteins in the frontal and temporal lobes. Up to 40% of FTLD patients reports a family history of neurodegeneration, and approximately 1/3 of familial cases shows an autosomal dominant pattern of inheritance of the phenotype. Over the past two decades, several causative and susceptibility genes for FTLD have been discovered, supporting the notion that genetic factors are important contributors to the disease processes...
January 2017: Functional Neurology
https://www.readbyqxmd.com/read/28361938/hippo-interferes-with-antiviral-defences
#16
Natalia Muñoz-Wolf, Ed C Lavelle
The Hippo pathway responds to environmental factors including nutrient availability, cell density and substrate stiffness to regulate organ size. This pathway is now shown to also regulate antiviral defence by modulating the TBK1-mediated control of interferon production.
March 31, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28356390/the-kinase-tbk1-functions-in-dendritic-cells-to-regulate-t-cell-homeostasis-autoimmunity-and-antitumor-immunity
#17
Yichuan Xiao, Qiang Zou, Xiaoping Xie, Ting Liu, Haiyan S Li, Zuliang Jie, Jin Jin, Hongbo Hu, Ganiraju Manyam, Li Zhang, Xuhong Cheng, Hui Wang, Isabelle Marie, David E Levy, Stephanie S Watowich, Shao-Cong Sun
Dendritic cells (DCs) are crucial for mediating immune responses but, when deregulated, also contribute to immunological disorders, such as autoimmunity. The molecular mechanism underlying the function of DCs is incompletely understood. In this study, we have identified TANK-binding kinase 1 (TBK1), a master innate immune kinase, as an important regulator of DC function. DC-specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy...
March 29, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28346439/hippo-signalling-governs-cytosolic-nucleic-acid-sensing-through-yap-taz-mediated-tbk1-blockade
#18
Qian Zhang, Fansen Meng, Shasha Chen, Steven W Plouffe, Shiying Wu, Shengduo Liu, Xinran Li, Ruyuan Zhou, Junxian Wang, Bin Zhao, Jianming Liu, Jun Qin, Jian Zou, Xin-Hua Feng, Kun-Liang Guan, Pinglong Xu
The Hippo pathway senses cellular conditions and regulates YAP/TAZ to control cellular and tissue homeostasis, while TBK1 is central for cytosolic nucleic acid sensing and antiviral defence. The correlation between cellular nutrient/physical status and host antiviral defence is interesting but not well understood. Here we find that YAP/TAZ act as natural inhibitors of TBK1 and are vital for antiviral physiology. Independent of transcriptional regulation and through the transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus-induced TBK1 activation, by preventing TBK1 Lys63-linked ubiquitylation and the binding of adaptors/substrates...
April 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28325821/phosphorylation-of-the-exocyst-protein-exo84-by-tbk1-promotes-insulin-stimulated-glut4-trafficking
#19
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
#20
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
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