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Nurbek Mambetsariev, Wai W Lin, Alicia M Wallis, Laura L Stunz, Gail A Bishop
The adaptor protein TNF receptor-associated factor 3 (TRAF3) is a critical regulator of B lymphocyte survival. B cell-specific TRAF3 deficiency results in enhanced viability and is associated with development of lymphoma and multiple myeloma. We show that TRAF3 deficiency led to induction of two proteins important for glucose metabolism, Glut1 and Hexokinase 2 (HXK2). This was associated with increased glucose uptake. In the absence of TRAF3, anaerobic glycolysis and oxidative phosphorylation were increased in B cells without changes in mitochondrial mass or reactive oxygen species...
October 18, 2016: Scientific Reports
Yu Chen, Xiaoling Deng, Junfang Deng, Jiehua Zhou, Yuping Ren, Shengxuan Liu, Deborah J Prusak, Thomas G Wood, Xiaoyong Bao
Human metapneumovirus (hMPV) is a major cause of lower respiratory infection in young children. Repeated infections occur throughout life, but its immune evasion mechanisms are largely unknown. We recently found that hMPV M2-2 protein elicits immune evasion by targeting mitochondrial antiviral-signaling protein (MAVS), an antiviral signaling molecule. However, the molecular mechanisms underlying such inhibition are not known. Our mutagenesis studies revealed that PDZ-binding motifs, 29-DEMI-32 and 39-KEALSDGI-46, located in an immune inhibitory region of M2-2, are responsible for M2-2-mediated immune evasion...
October 13, 2016: Virology
E Budisova Svandova, B Vesela, H Lesot, A Poliard, E Matalova
Elimination of the interdigital web is considered to be the classical model for assessing apoptosis. So far, most of the molecules described in the process have been connected to the intrinsic (mitochondrial) pathway. The extrinsic (receptor mediated) apoptotic pathway has been rather neglected, although it is important in development, immunomodulation and cancer therapy. This work aimed to investigate factors of the extrinsic apoptotic machinery during interdigital regression with a focus on three crucial initiators: Fas, Fas ligand and caspase-8...
October 5, 2016: Histochemistry and Cell Biology
Wanwan Huai, Hui Song, Zhongxia Yu, Wenwen Wang, Lihui Han, Takeharu Sakamoto, Motoharu Seiki, Lining Zhang, Qunye Zhang, Wei Zhao
Type I IFNs (IFN-α/β) play crucial roles in the elimination of invading viruses. Multiple immune cells including macrophages recognize viral infection through a variety of pattern recognition receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors, and initiate type I IFN secretion and subsequent antiviral immune responses. However, the mechanisms by which host immune cells can produce adequate amounts of type I IFNs and then eliminate viruses effectively remain to be further elucidated...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Qin Yang, Maren J Pröll, Dessie Salilew-Wondim, Rui Zhang, Dawit Tesfaye, Huitao Fan, Mehmet U Cinar, Christine Große-Brinkhaus, Ernst Tholen, Mohammad A Islam, Michael Hölker, Karl Schellander, Muhammad J Uddin, Christiane Neuhoff
Pulmonary alveolar macrophages (AMs) are important in defense against bacterial lung inflammation. Cluster of differentiation 14 (CD14) is involved in recognizing bacterial lipopolysaccharide (LPS) through MyD88-dependent and TRIF pathways of innate immunity. Sulforaphane (SFN) shows anti-inflammatory activity and suppresses DNA methylation. To identify CD14 epigenetic changes by SFN in the LPS-induced TRIF pathway, an AMs model was investigated in vitro CD14 gene expression was induced by 5 µg/ml LPS at the time point of 12 h and suppressed by 5 µM SFN...
September 29, 2016: Innate Immunity
Surasak Jittavisutthikul, Watee Seesuay, Jeeraphong Thanongsaksrikul, Kanyarat Thueng-In, Potjanee Srimanote, Rolf G Werner, Wanpen Chaicumpa
A safe and effective direct acting anti-hepatitis C virus (HCV) agent is still needed. In this study, human single chain variable fragments of antibody (scFvs) that bound to HCV NS3/4A protein were produced by phage display technology. The engineered scFvs were linked to nonaarginines (R9) for making them cell penetrable. HCV-RNA-transfected Huh7 cells treated with the transbodies produced from four different transformed E. coli clones had reduced HCV-RNA inside the cells and in the cell spent media, as well as fewer HCV foci in the cell monolayer compared to the transfected cells in culture medium alone...
2016: Frontiers in Immunology
Meijuan Zou, Fang Wang, Aiqin Jiang, Anliang Xia, Siya Kong, Chun Gong, Mingxia Zhu, Xin Zhou, Jun Zhu, Wei Zhu, Wenfang Cheng
BACKGROUND: Helicobacter pylori infection is the main cause of chronic gastritis, peptic ulcer, and gastric cancer. Tip-α is a newly identified carcinogenic factor present in H. pylori. TRAF3 can activate NF-κB by both canonical and noncanonical signaling pathways. In this study, we found that the expression of TRAF3 and NF-κB was upregulated, while microRNA-3178 (miR-3178) was decreased in H. pylori-positive gastric tissues but not in H. pylori-negative tissues. MATERIALS AND METHODS: GES-1 cells were incubated with 12...
August 5, 2016: Helicobacter
Manjunath Yariswamy, Tadashi Yoshida, Anthony J Valente, Hemanth Kumar Kandikattu, Siva S V P Sakamuri, Jalahalli M Siddesha, Sergiy Sukhanov, Zubaida Saifudeen, Lixin Ma, Ulrich Siebenlist, Jason D Gardner, Bysani Chandrasekar
TRAF3IP2 (TRAF3 interacting protein 2; previously known as CIKS or Act1) is a key intermediate in the normal inflammatory response and the pathogenesis of various autoimmune and inflammatory diseases. Induction of TRAF3IP2 activates IκB kinase (IKK)/NF-κB, JNK/AP-1, and c/EBPβ and stimulates the expression of various inflammatory mediators with negative myocardial inotropic effects. To investigate the role of TRAF3IP2 in heart disease, we generated a transgenic mouse model with cardiomyocyte-specific TRAF3IP2 overexpression (TRAF3IP2-Tg)...
September 9, 2016: Journal of Biological Chemistry
Yuxuan Miao, Jianxuan Wu, Soman N Abraham
Although the intracellular trafficking system is integral to most physiologic activities, its role in mediating immune responses to infection has remained elusive. Here, we report that infected bladder epithelial cells (BECs) mobilized the exocyst complex, a powerful exporter of subcellular vesicles, to rapidly expel intracellular bacteria back for clearance. Toll-like receptor (TLR) 4 signals emanating from bacteria-containing vesicles (BCVs) were found to trigger K33-linked polyubiquitination of TRAF3 at Lys168, which was then detected by RalGDS, a guanine nucleotide exchange factor (GEF) that precipitated the assembly of the exocyst complex...
July 19, 2016: Immunity
Katharina L Willmann, Roberto Sacco, Rui Martins, Wojciech Garncarz, Ana Krolo, Sylvia Knapp, Keiryn L Bennett, Kaan Boztug
NF-κB signaling is a central pathway of immunity and integrates signal transduction upon a wide array of inflammatory stimuli. Noncanonical NF-κB signaling is activated by a small subset of TNF family receptors and characterized by NF-κB2/p52 transcriptional activity. The medical relevance of this pathway has recently re-emerged from the discovery of primary immunodeficiency patients that have loss-of-function mutations in the MAP3K14 gene encoding NIK. Nevertheless, knowledge of protein interactions that regulate noncanonical NF-κB signaling is sparse...
September 2, 2016: Journal of Proteome Research
Xiaofei Gao, Thanh H Pham, Leigh Ann Feuerbacher, Kangming Chen, Michael P Hays, Gyanendra Singh, Christian Rueter, Ramon Hurtado-Guerrero, Philip R Hardwidge
Interferon signaling plays important roles in both intestinal homeostasis and in the host response to pathogen infection. The extent to which bacterial pathogens inhibit this host pathway is an understudied area of investigation. We characterized Citrobacter rodentium strains bearing deletions in individual type III secretion system effector genes to determine whether this pathogen inhibits the host type I IFN response and which effector is responsible. The NleB effector limited host IFN-β production by inhibiting Lys(63)-linked ubiquitination of TNF receptor-associated factor 3 (TRAF3)...
August 26, 2016: Journal of Biological Chemistry
Peizhi Li, Hongxiang Liu, Yiyin Zhang, Rui Liao, Kun He, Xiongzhong Ruan, Jianping Gong
Pellino 1 positively regulates Toll-like receptor 4 signaling by regulating tumor necrosis factor receptor-associated factor 3 (TRAF3) degradation and is suppressed with the induction of endotoxin tolerance. However, the role of TRAF3 in endotoxin tolerance is largely unknown. In this study, we found that lipopolysaccharide (LPS) stimulation decreased TARF3 protein expression in mouse Kupffer cells (KCs) and liver tissues, whereas endotoxin tolerization abrogated this effect. Degradative TRAF3 K48-linked ubiquitination and the cytoplasmic translocation of the MYD88-associated multiprotein complex were significantly inhibited in tolerized KCs, which led to markedly impaired activation of MYD88-dependent JNK and p38 and downregulation of inflammatory cytokines...
September 15, 2016: Journal of Infectious Diseases
Muhammad Jasim Uddin, Willy W Suen, Angela Bosco-Lauth, Airn-Elizabeth Hartwig, Roy A Hall, Richard A Bowen, Helle Bielefeldt-Ohmann
West Nile virus (WNV) is one of the most common causes of epidemic viral encephalitis in horses worldwide. Peripheral blood mononuclear cells (PBMCs) are amongst the first to encounter the virus following a mosquito bite. This study aimed to elucidate the transcription kinetics of cytokine, Toll-like receptor (TLRs) and TLRs-associated genes following WNV challenge of equine PBMCs. PBMCs were challenged with an Australian strain of WNV (WNVNSW2011) and transcriptomes were quantified at 2, 6, 12 and 24 h post-infection (pi) using qRT-PCR...
2016: Veterinary Research
Siva Sankara Vara Prasad Sakamuri, Yusuke Higashi, Sergiy Sukhanov, Jalahalli M Siddesha, Patrice Delafontaine, Ulrich Siebenlist, Bysani Chandrasekar
BACKGROUND AND AIMS: Atherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development. METHODS: TRAF3IP2/ApoE double knockout (DKO) mice were generated by crossing TRAF3IP2(-/-) and ApoE(-/-) mice...
September 2016: Atherosclerosis
He-Ting Mao, Yan Wang, Juan Cai, Jun-Ling Meng, Yu Zhou, Yu Pan, Xiao-Ping Qian, Yu Zhang, Jun Zhang
During virus infection, the cascade signaling pathway that leads to the production of proinflammatory cytokines is controlled at multiple levels to avoid detrimental overreaction. HACE1 has been characterized as an important tumor suppressor. Here, we identified HACE1 as an important negative regulator of virus-triggered type I IFN signaling. Overexpression of HACE1 inhibited Sendai virus- or poly (I:C)-induced signaling and resulted in reduced IFNB1 production and enhanced virus replication. Knockdown of HACE1 expression exhibited the opposite effects...
2016: Viruses
Emine Guven-Maiorov, Ozlem Keskin, Attila Gursoy, Carter VanWaes, Zhong Chen, Chung-Jung Tsai, Ruth Nussinov
BACKGROUND: The tumor necrosis factor receptor (TNFR) associated factor 3 (TRAF3) is a key node in innate and adaptive immune signaling pathways. TRAF3 negatively regulates the activation of the canonical and non-canonical NF-κB pathways and is one of the key proteins in antiviral immunity. SCOPE OF REVIEW: Here we provide a structural overview of TRAF3 signaling in terms of its competitive binding and consequences to the cellular network. For completion, we also include molecular mimicry of TRAF3 physiological partners by some viral proteins...
November 2016: Biochimica et Biophysica Acta
Shih-Wen Li, Ching-Ying Wang, Yu-Jen Jou, Su-Hua Huang, Li-Hsin Hsiao, Lei Wan, Ying-Ju Lin, Szu-Hao Kung, Cheng-Wen Lin
Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLPro) reportedly inhibits the production of type I interferons (IFNs) and pro-inflammatory cytokines in Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene 1 (RIG-I) pathways. The study investigated the inhibitory effect and its antagonistic mechanism of SARS-CoV PLPro on TLR7-mediated cytokine production. TLR7 agonist (imiquimod (IMQ)) concentration-dependently induced activation of ISRE-, NF-κB- and AP-1-luciferase reporters, as well as the production of IFN-α, IFN-β, TNF-α, IL-6 and IL-8 in human promonocyte cells...
2016: International Journal of Molecular Sciences
Gail A Bishop
This review summarizes the current state of knowledge regarding the roles of the signaling adapter protein tumor necrosis factor receptor (TNFR)-associated factor 3 in regulating the functions of B and T lymphocytes. In B lymphocytes, TNFR-associated factor 3 inhibits signaling by TNFR superfamily receptors, Toll-like receptors, and interleukin-6R. In contrast, signaling to B cells by the virally encoded oncogenic protein latent membrane protein 1 is promoted by TNFR-associated factor 3. An important B cell-specific role for TNFR-associated factor 3 is the inhibition of homeostatic survival, directly relevant to the common occurrence of TNFR-associated factor 3 mutations in human B cell malignancies...
May 6, 2016: Journal of Leukocyte Biology
Christophe Pedros, Yaoyang Zhang, Joyce K Hu, Youn Soo Choi, Ann J Canonigo-Balancio, John R Yates, Amnon Altman, Shane Crotty, Kok-Fai Kong
Signaling via the inducible costimulator ICOS fuels the stepwise development of follicular helper T cells (TFH cells). However, a signaling pathway unique to ICOS has not been identified. We found here that the kinase TBK1 associated with ICOS via a conserved motif, IProx, that shares homology with the tumor-necrosis-factor receptor (TNFR)-associated factors TRAF2 and TRAF3. Disruption of this motif abolished the association of TBK1 with ICOS, TRAF2 and TRAF3, which identified a TBK1-binding consensus. Alteration of this motif in ICOS or depletion of TBK1 in T cells severely impaired the differentiation of germinal center (GC) TFH cells and the development of GCs, interfered with B cell differentiation and disrupted the development of antibody responses, but the IProx motif and TBK1 were dispensable for the early differentiation of TFH cells...
July 2016: Nature Immunology
Davina Derous, Sharon E Mitchell, Cara L Green, Yingchun Wang, Jing Dong J Han, Luonan Chen, Daniel E L Promislow, David Lusseau, John R Speakman, Alex Douglas
Connectivity in a gene-gene network declines with age, typically within gene clusters. We explored the effect of short-term (3 months) graded calorie restriction (CR) (up to 40 %) on network structure of aging-associated genes in the murine hypothalamus by using conditional mutual information. The networks showed a topological rearrangement when exposed to graded CR with a higher relative within cluster connectivity at 40CR. We observed changes in gene centrality concordant with changes in CR level, with Ppargc1a, and Ppt1 having increased centrality and Etfdh, Traf3 and Abcc1 decreased centrality as CR increased...
May 2016: Aging
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