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Xiaojuan Chen, Qian Zhao, Xie Qing, Yaling Xing, Zhongbin Chen
IFNβ innate immune plays an essential role in antiviral immune. Previous reports suggested that many important regulatory proteins in innate immune pathway may be modified by ubiquitin and that many de-ubiquitination (DUB) proteins may affect immunity. Monocyte chemotactic protein-inducing protein 1 (MCPIP1), one of the CCCH Zn finger-containing proteins, was reported to have DUB function, but its effect on IFNβ innate immune was not fully understood. In this study, we uncovered a novel mechanism that may explain how MCPIP1 efficiently inhibits IFNβ innate immune...
June 16, 2018: Biochemical and Biophysical Research Communications
Fubing Li, Yang Li, Huichun Liang, Tao Xu, Yanjie Kong, Maobo Huang, Ji Xiao, Xi Chen, Houjun Xia, Yingying Wu, Zhongmei Zhou, Xiaomin Guo, Chunmiao Hu, Chuanyu Yang, Xu Cheng, Ceshi Chen, Xiaopeng Qi
Lysine-63 (K63)-linked polyubiquitination of TRAF3 coordinates the engagement of pattern recognition receptors to recruited adaptor proteins and downstream activator TBK1 in pathways that induce type I interferon (IFN). Whether auto-ubiquitination or other E3 ligases mediate K63-linked TRAF3 polyubiquitination remains unclear. We demonstrated that mice deficient in E3 ligase gene Hectd3 remarkably increased host defense against infection by intracellular bacteria F. novicida, Mycobacterium, and Listeria by limiting bacterial dissemination...
June 19, 2018: Journal of Clinical Investigation
Tian-Sheng He, Tian Chen, Dan-Dan Wang, Liang-Guo Xu
Mitochondrial anti‑viral signaling protein (VISA), additionally termed MAVS, IPS‑1 and Cardif, is located at the outer membrane of mitochondria and is an essential adaptor in the Rig‑like receptor (RLRs) signaling pathway. Upon viral infection, activated RLRs interact with VISA on mitochondria, forming a RLR‑VISA platform, leading to the recruitment of different TRAF family members, including TRAF3, TRAF2 and TRAF6. This results in the phosphorylation and nuclear translocation of interferon regulatory factors 3 and 7 (IRF3/IRF7) by TANK binding kinase 1 (TBK1) and/or IKKε, as well as activation of NF‑κB, to induce type I interferons (IFNs) and pro‑inflammatory cytokines...
June 15, 2018: Molecular Medicine Reports
Long Yang, Leilei Wang, Harshada Ketkar, Jinzhu Ma, Guang Yang, Shuang Cui, Tingting Geng, Dana G Mordue, Toyoshi Fujimoto, Gong Cheng, Fuping You, Rongtuan Lin, Erol Fikrig, Penghua Wang
The ubiquitin regulatory X domain-containing proteins (UBXNs) are likely involved in diverse biological processes. Their physiological functions, however, remain largely unknown. Here we present physiological evidence that UBXN3B positively regulates stimulator-of-interferon genes (STING) signaling. We employ a tamoxifen-inducible Cre-LoxP approach to generate systemic Ubxn3b knockout in adult mice as the Ubxn3b-null mutation is embryonically lethal. Ubxn3b-/- , like Sting-/- mice, are highly susceptible to lethal herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) infection, which is correlated with deficient immune responses when compared to Ubxn3b+/+ littermates...
June 13, 2018: Nature Communications
Emari Ogawa, Kojiro Mukai, Kota Saito, Hiroyuki Arai, Tomohiko Taguchi
Stimulator of interferon genes (STING) is essential for the type I interferon and pro-inflammatory responses against DNA pathogens. In response to the presence of cytosolic DNA, STING translocates from the endoplasmic reticulum (ER) to the Golgi, and activates TANK-binding kinase 1 (TBK1), a cytosolic kinase that is essential for the activation of STING-dependent downstream signalling. The organelles where TBK1 binds to STING remain unknown. Here we show that TBK1 binds to STING at the Golgi, not at the ER...
June 2, 2018: Biochemical and Biophysical Research Communications
Kaixuan Cui, Shanshan Zhang, Xiaojuan Liu, Zhenzhen Yan, Lili Huang, Xiaowei Yang, Rongrong Zhu, Aimin Sang
choroidal neovascularization (CNV), a characteristic of wet age-related macular degeneration (AMD), causes severe vision loss among elderly patients. TANK-binding kinase 1 (TBK1) is a ubiquitously expressed serine-threonine kinase and is found to induce endothelial cells proliferation, represent a novel mediator of tumor angiogenesis and exert pro-inflammatory effect. However, the role of TBK1 in choroidal neovascularization has not been investigated so far. In this study, we found that the expression of TBK1 and VEGF was up-regulated in RF/6 A cells chemical hypoxia model and laser-induced mouse CNV model...
June 1, 2018: Biochemical and Biophysical Research Communications
Federica Perrone, Rita Cacace, Sara Van Mossevelde, Tobi Van den Bossche, Peter P De Deyn, Patrick Cras, Sebastiaan Engelborghs, Julie van der Zee, Christine Van Broeckhoven
In a prospective study of dementia in Flanders (Belgium), we observed a substantial fraction of early-onset dementia patients who did not fulfill the criteria for a specific dementia subtype, leaving the patients without a precise clinical diagnosis. We selected 211 of these patients for genetic testing of causal genes linked to neurodegenerative brain diseases. In this group, the onset or inclusion age was 59.9 ± 8.2 years and 27.4% had a positive family history. We used a panel of 16 major genes linked to Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's disease, and prion diseases...
May 9, 2018: Neurobiology of Aging
Michelle M Coleman, Sharee A Basdeo, Amy M Coleman, Clíona Ní Cheallaigh, Celia Peral de Castro, Anne Marie McLaughlin, Padraic J Dunne, James Harris, Joseph Keane
Vitamin A deficiency strongly predicts the risk of developing tuberculosis (TB) in individuals exposed to Mycobacterium tuberculosis (Mtb). The burden of antibiotic resistant TB is increasing globally therefore there is an urgent need to develop host-directed adjunctive therapies to treat TB. Alveolar macrophages (AM), the niche cell for Mtb, metabolize vitamin A to all-trans retinoic acid (atRA), which influences host immune responses. We sought to determine the mechanistic effects of atRA on the host immune response to intracellular bacterial infection in primary human and murine macrophages...
May 31, 2018: American Journal of Respiratory Cell and Molecular Biology
Jiehua Wang, Min Dai, Yange Cui, Guojun Hou, Jun Deng, Xin Gao, Zhuojun Liao, Ya Liu, Yao Meng, Lingling Wu, Chao Yao, Yan Wang, Jie Qian, Qiang Guo, Huihua Ding, Bo Qu, Nan Shen
OBJECTIVE: Increasing evidence indicate a critical pathogenic role of cGAS-STING signaling pathway in systemic lupus erythematosus (SLE). Interferon(IFN) inducible gene, IFIT3, is elevated in SLE. However, it is still not clear how IFIT3 contributes to SLE pathogenesis. We undertook this study to investigate the activation of cGAS-STING signaling pathway in SLE monocytes, as well as how elevated IFIT3 contributes to the overactivation of cGAS-STING signaling pathway. METHODS: Monocytes from SLE patients or healthy controls were examined for the activity of cGAS-STING signaling pathway and expression of IFIT3...
May 27, 2018: Arthritis & Rheumatology
Qi Yang, Jielin Tang, Rongjuan Pei, XiaoXiao Gao, Jing Guo, Chonghui Xu, Yun Wang, Qian Wang, Chunchen Wu, Yuan Zhou, Xue Hu, He Zhao, Yanyi Wang, Xinwen Chen, Jizheng Chen
Class II HDACs, such as HDAC4, are critical regulators of the immune response in various immune cells; however, its role in innate immunity remains largely unknown. Here, we report that the overexpression of HDAC4 suppresses the production of type I interferons triggered by pattern-recognition receptors (PRRs). HDAC4 repressed the translocation of transcription factor IRF3 to the nucleus, thereby decreasing IRF3-mediated IFN-β expression. In particular, we also determined that HDAC4 can be phosphorylated and simultaneously block the phosphorylation of IRF3 at Ser386 and Ser396 by TBK1 and IKKε, respectively, by interacting with the kinase domain of TBK1 and IKKε...
May 25, 2018: Journal of Molecular Cell Biology
Eunji Kim, Ju Y Yoon, Jongsung Lee, Deok Jeong, Jae G Park, Yo H Hong, Ji H Kim, Adithan Aravinthan, Jong-Hoon Kim, Jae Y Cho
Inflammation is a response that protects the body from pathogens. Through several inflammatory signaling pathways mediated by various families of transcription factors, such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), interferon regulatory factors (IRFs), and signal transducers and activators of transcription (STATs), various inflammatory cytokines and chemokines are induced and inflammatory responses are boosted. Simultaneously, inhibitory systems are activated and provide negative feedback...
May 24, 2018: Journal of Cellular Physiology
Zhen-Hu Liu, Hong-Bo Liu, Jun Wang
Although pathologic hypertrophic hearts currently maintain output, sustained cardiac hypertrophy could predispose a patient to arrhythmia and sudden death, and also cause heart failure. Thus, finding effective treatment and exploring the underlying molecular mechanisms of cardiac hypertrophy is urgently necessary. Astragaloside IV (AST-IV) is the main active component, extracted from the traditional Chinese medicinal herb Astragalus membranaceus. Previous studies have indicated that AST-IV has various bioactivities, such as anti-cancer, anti-oxidative stress and anti-inflammation...
January 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Jiansheng Li, Mingqing Lu, Bei Huang, Yingjun Lv
Interferon (IFN)-mediated antiviral response is an important part of host defense. Previous studies reported that porcine circovirus type 2 (PCV2) inhibits interferon production, but the mechanism is still poorly understood. In this study, PCV2 suppresses IFN-β and IRF3 promoters and mRNA level of IFN-β induced by ISD or Poly(I:C), but has no effect on the activation of AP-1 and NF-κB. Furthermore, PCV2 decreases the mRNA level of IFN-β and IFN-β promoter activity driven by STING, TBK1, IRF3, and IRF3/5D, and causes a reduction in the protein level of nuclear p-IRF3...
May 21, 2018: Virology
Seok Hyun Eom, So-Jung Jin, Hee-Yeong Jeong, Youngju Song, You Jin Lim, Jong-In Kim, Youn-Hyung Lee, Hee Kang
Kudzu ( Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep) is a perennial leguminous vine, and its root and flower have been used for herbal medicine in Asia for a long time. Most dietary flavonoids are reported to be concentrated in its root, not in its aerial parts including leaves. In this study, we investigated whether kudzu leaf and its major constituent, robinin (kaempferol-3- O -robinoside-7- O -rhanmoside) possessed anti-inflammatory activity. To test this hypothesis, we used peritoneal macrophages isolated from BALB/c mice and stimulated the cells with lipopolysaccharide (LPS) or LPS plus interferon (IFN)-γ...
May 22, 2018: International Journal of Molecular Sciences
Sara Van Mossevelde, Sebastiaan Engelborghs, Julie van der Zee, Christine Van Broeckhoven
Frontotemporal lobar degeneration (FTLD) represents a group of neurodegenerative brain diseases with highly heterogeneous clinical, neuropathological and genetic characteristics. This high degree of heterogeneity results from the presence of several different underlying molecular disease processes; consequently, it is unlikely that all patients with FTLD will benefit from a single therapy. Therapeutic strategies for FTLD are currently being explored, and tools are urgently needed that enable the selection of patients who are the most likely to benefit from a particular therapy...
May 18, 2018: Nature Reviews. Neurology
Xin Wei, Kin-Sang Cho, Eric F Thee, Martine J Jager, Dong Feng Chen
Glaucoma is a complex neurodegenerative disease with many clinical subtypes. Some of its rare forms include pigmentary glaucoma, uveitic glaucoma and congenital glaucoma. While they all share common features of progressive retinal ganglion cell (RGC) loss, optic nerve damage and corresponding visual field loss, the exact mechanisms underlying glaucomatous neuron loss are not clear. This has largely hindered the development of a real cure for this disease. Elevated intraocular pressure (IOP) is a known major risk factor of glaucoma; however, progressive degeneration of RGCs and axons can also be found in patients with a normal IOP, i...
May 18, 2018: Journal of Neuroscience Research
Puxian Fang, Liurong Fang, Jie Ren, Yingying Hong, Xiaorong Liu, Yunyang Zhao, Dang Wang, Guiqing Peng, Shaobo Xiao
Porcine deltacoronavirus (PDCoV) has recently emerged as an enteric pathogen that can cause serious vomiting and diarrhea in suckling piglets. The first outbreak of PDCoV occurred in the United States in 2014 and was followed by reports of PDCoV in South Korea, China, Thailand, Lao people's Democratic Republic, and Vietnam, leading to economic losses for pig farms and posing considerable threat to the swine industry worldwide. Our previous studies have shown that PDCoV encodes three accessory proteins, NS6, NS7, and NS7a, but the functions of these proteins in viral replication, pathogenesis, and immune regulation remain unclear...
May 16, 2018: Journal of Virology
Hiroki Tsukamoto, Shino Takeuchi, Kanae Kubota, Yohei Kobayashi, Sao Kozakai, Ippo Ukai, Ayumi Shichiku, Misaki Okubo, Muneo Numasaki, Yoshitomi Kanemitsu, Yotaro Matsumoto, Tomonori Nochi, Kouichi Watanabe, Hisashi Aso, Yoshihisa Tomioka
Toll-like receptor 4 (TLR4) is an indispensable immune receptor for lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall. Following LPS stimulation, TLR4 transmits the signal from the cell surface and becomes internalized in an endosome. However, the spatial regulation of TLR4 signaling is not fully understood. Here, we investigated the mechanisms of LPS-induced TLR4 internalization and clarified the roles of the extracellular LPS-binding molecules, LPS-binding protein (LBP), and glycerophosphatidylinositol-anchored protein (CD14)...
May 14, 2018: Journal of Biological Chemistry
Marie Lork, Marja Kreike, Jens Staal, Rudi Beyaert
CYLD is a deubiquitinating enzyme that plays a crucial role in immunity and inflammation as a negative regulator of NF-κB transcription factor and JNK kinase signaling. Defects in either of these pathways contribute to the progression of numerous inflammatory and autoimmune disorders. Therefore, we set out to unravel molecular mechanisms that control CYLD activity in the context of T cell receptor (TCR) signaling. More specifically, we focused on CYLD phosphorylation at Ser418, which can be detected upon immunoblotting of cell extracts with phospho(Ser418)-CYLD specific antibodies...
2018: Frontiers in Cell and Developmental Biology
Ahmed Outlioua, Marie Pourcelot, Damien Arnoult
After a viral infection and the stimulation of some pattern-recognition receptors as the toll-like receptor 3 in the endosomes or the RIG-I-like receptors in the cytosol, activation of the IKK-related kinase TBK1 leads to the production of type I interferons (IFNs) after phosphorylation of the transcription factors IRF3 and IRF7. Recent findings indicate an involvement of K63-linked polyubiquitination and of the Golgi-localized protein optineurin (OPTN) in the activation of this crucial kinase involved in innate antiviral immunity...
2018: Frontiers in Immunology
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