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https://www.readbyqxmd.com/read/28717359/the-c-terminal-effector-domain-of-non-structural-protein-1-of-influenza-a-virus-blocks-ifn-%C3%AE-production-by-targeting-tnf-receptor-associated-factor-3
#1
Wei Qian, Xiaoqin Wei, Kelei Guo, Yongtao Li, Xian Lin, Zhong Zou, Hongbo Zhou, Meilin Jin
Influenza A virus non-structural protein 1 (NS1) antagonizes interferon response through diverse strategies, particularly by inhibiting the activation of interferon regulatory factor 3 (IRF3) and IFN-β transcription. However, the underlying mechanisms used by the NS1 C-terminal effector domain (ED) to inhibit the activation of IFN-β pathway are not well understood. In this study, we used influenza virus subtype of H5N1 to demonstrate that the NS1 C-terminal ED but not the N-terminal RNA-binding domain, binds TNF receptor-associated factor 3 (TRAF3)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28717003/surface-toll-like-receptor-3-expression-in-metastatic-intestinal-epithelial-cells-induces-inflammatory-cytokine-production-and-promotes-invasiveness
#2
Marit Bugge, Bjarte Bergstrom, Oda Kamilla Eide, Helene Solli, Ingrid F Kjønstad, Jørgen Stenvik, Terje Espevik, Nadra J Nilsen
Toll-like receptors (TLR)s are innate immune receptors for sensing microbial molecules and damage-associated molecular patterns released from host cells. Double-stranded RNA and the synthetic analog polyinosinic:polycytidylic acid (Poly(I:C)) bind and activate TLR3. This stimulation leads to recruitment of the adaptor molecule TRIF and activation of the transcription factors nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF-3), classically inducing IFNβ production. Here, we report that unlike non-metastatic intestinal epithelial cells (IECs), metastatic IECs express TLR3, and that TLR3 promotes invasiveness of these cells...
July 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28714988/snp-mediated-disruption-of-ctcf-binding-at-the-ifitm3-promoter-is-associated-with-risk-of-severe-influenza-in-humans
#3
E Kaitlynn Allen, Adrienne G Randolph, Tushar Bhangale, Pranay Dogra, Maikke Ohlson, Christine M Oshansky, Anthony E Zamora, John P Shannon, David Finkelstein, Amy Dressen, John DeVincenzo, Miguela Caniza, Ben Youngblood, Carrie M Rosenberger, Paul G Thomas
Previous studies have reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism by which risk is conferred remain controversial. We prioritized SNPs in IFITM3 on the basis of putative biological function and identified rs34481144 in the 5' UTR. We found evidence of a new association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined a role for rs34481144 as an expression quantitative trait locus (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression...
July 17, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28712728/hexim1-and-neat1-long-non-coding-rna-form-a-multi-subunit-complex-that-regulates-dna-mediated-innate-immune-response
#4
Mehdi Morchikh, Alexandra Cribier, Raoul Raffel, Sonia Amraoui, Julien Cau, Dany Severac, Emeric Dubois, Olivier Schwartz, Yamina Bennasser, Monsef Benkirane
The DNA-mediated innate immune response underpins anti-microbial defenses and certain autoimmune diseases. Here we used immunoprecipitation, mass spectrometry, and RNA sequencing to identify a ribonuclear complex built around HEXIM1 and the long non-coding RNA NEAT1 that we dubbed the HEXIM1-DNA-PK-paraspeckle components-ribonucleoprotein complex (HDP-RNP). The HDP-RNP contains DNA-PK subunits (DNAPKc, Ku70, and Ku80) and paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATRIN3). We show that binding of HEXIM1 to NEAT1 is required for its assembly...
July 10, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28706136/swine-irf3-irf7-attenuates-inflammatory-responses-through-tlr4-signaling-pathway
#5
Pei-Ge Chen, Yan-Jing Guan, Guang-Ming Zha, Xian-Qin Jiao, He-Shui Zhu, Cheng-Yu Zhang, Yue-Ying Wang, He-Ping Li
To explore the role of IRF3/IRF7 during inflammatory responses, we investigated the effects of swine IRF3/IRF7 on TLR4 signaling pathway and inflammatory factors expression in porcine kidney epithelial PK15 cell lines. We successfully constructed eukaryotic vectors PB-IRF3 and PB-IRF7, transfected these vectors into PK15 cells and observed GFP under a fluorescence microscope. In addition, RT-PCR was also used to detect transfection efficiency. We found that IRF3/IRF7 was efficiently overexpressed in PK15 cells...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28704656/induction-of-inkit-by-viral-infection-negatively-regulates-antiviral-responses-through-inhibiting-phosphorylation-of-p65-and-irf3
#6
Bin Lu, Yujie Ren, Xueqin Sun, Cuijuan Han, Hongyan Wang, Yuxuan Chen, Qianqian Peng, Yongbo Cheng, Xiaoliang Cheng, Qiyun Zhu, Wenxin Li, Hong-Liang Li, Hai-Ning Du, Bo Zhong, Zan Huang
The transcription factors p65 and IRF3 play key roles in the induction of cellular antiviral responses. Phosphorylation of p65 and IRF3 is required for their activity and constitutes a key checkpoint. Here we report that viral infection induced upregulation of INKIT, an inhibitor for NF-κB and IRF3 that restricted innate antiviral responses by blocking phosphorylation of p65 and IRF3. INKIT overexpression inhibited virus-induced phosphorylation of p65 and IRF3 and expression of downstream genes. In contrast, knockdown or knockout of INKIT had the opposite effect: Inkit(-/-) mice produced elevated levels of type I interferons and proinflammatory cytokines and were more resistant to lethal viral infection compared to wild-type...
July 12, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28698384/palmitic-acid-dysregulates-the-hippo-yap-pathway-and-inhibits-angiogenesis-by-inducing-mitochondrial-damage-and-activating-the-cytosolic-dna-sensor-cgas-sting-irf3-signaling
#7
Liangshuai Yuan, Yun Mao, Wei Luo, Weiwei Wu, Hao Xu, Xing Li Wang, Ying H Shen
Impaired angiogenesis and wound healing carry significant morbidity and mortality in diabetic patients. Metabolic stress from hyperglycemia and elevated free fatty acids have been shown to inhibit endothelial angiogenesis. However, the underlying mechanisms remain poorly understood. In this study, we show that dysregulation of the Hippo-YAP pathway, an important signaling in regulating tissue repair and regeneration, underlies palmitic acid (PA) -induced inhibition of endothelial angiogenesis. PA inhibited endothelial cell proliferation, migration and tube formation, which were associated with increased MST1 expression, YAP phosphorylation/inactivation and nuclear exclusion...
July 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28683323/identification-of-a-druggable-pathway-controlling-glioblastoma-invasiveness
#8
Nora Pencheva, Mark C de Gooijer, Daniel J Vis, Lodewyk F A Wessels, Tom Würdinger, Olaf van Tellingen, René Bernards
Diffuse and uncontrollable brain invasion is a hallmark of glioblastoma (GBM), but its mechanism is understood poorly. We developed a 3D ex vivo organotypic model to study GBM invasion. We demonstrate that invading GBM cells upregulate a network of extracellular matrix (ECM) components, including multiple collagens, whose expression correlates strongly with grade and clinical outcome. We identify interferon regulatory factor 3 (IRF3) as a transcriptional repressor of ECM factors and show that IRF3 acts as a suppressor of GBM invasion...
July 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28659477/west-nile-virus-ns1-antagonizes-interferon-%C3%AE-production-by-targeting-rig-i-and-mda5
#9
Hong-Lei Zhang, Han-Qing Ye, Si-Qing Liu, Cheng-Lin Deng, Xiao-Dan Li, Pei-Yong Shi, Bo Zhang
West Nile virus (WNV) is a mosquito-borne flavivirus that causes epidemics of encephalitis and viscerotropic disease worldwide. This virus has spread rapidly and has posed significant a public health threat since the outbreak in New York City in 1999. The interferon (IFN)-mediated antiviral response represents an important component of virus-host interactions and plays an essential role in regulating viral replication. Previous studies have suggested that multifunctional non-structural proteins encoded by flaviviruses antagonize the host IFN response via various means in order to establish efficient viral replication...
June 28, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28659470/hepatitis-c-virus-ns5a-targets-the-nucleosome-assembly-protein-nap1l1-to-control-the-innate-cellular-response
#10
Recep Emrah Çevik, Mia Cesarec, Ana Da Silva Filipe, Danilo Licastro, John McLauchlan, Alessandro Marcello
Hepatitis C virus (HCV) is a single-stranded positive-sense RNA hepatotropic virus. Despite cellular defenses, HCV is able to replicate in hepatocytes and to establish a chronic infection that could lead to severe complications and hepatocellular carcinoma. An important player in subverting the host response to HCV infection is the viral non-structural protein NS5A that, in addition to its role in replication and assembly, targets several pathways involved in the cellular response to viral infection. Several unbiased screens identified the nucleosome-assembly protein 1-like 1 (NAP1L1) as an interaction partner of HCV NS5A...
June 28, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28651742/strap-positively-regulates-tlr3-triggered-signaling-pathway
#11
Hyunbin D Huh, Eunhye Lee, Jinwook Shin, Boyoun Park, Sungwook Lee
Toll-like receptor (TLR) signaling drives the innate immune response by activating nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF). We have previously shown that STRAP interacts with TAK1 and IKKα along with NF-κB subunit p65, leading to the activation of pro-inflammatory cytokines. However, the roles of STRAP in TRIF/TBK1-mediated TLR3 activation and the subsequent type I interferon (IFN) production are not fully elucidated. Here, we demonstrate that STRAP acts as a scaffold protein in TLR3-triggered signaling...
June 19, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28651122/activation-of-irf3-contributes-to-ifn-%C3%AE-and-isg54-expression-during-the-immune-responses-to-b16f10-tumor-growth
#12
Zachary Guinn, Deborah M Brown, Thomas M Petro
Interferon Regulatory Factor (IRF-3) has been shown to contribute to immune control of B16 melanoma tumor growth. We have shown previously that IRF-3 has a role in IFN-γ-induced expression of pro-apoptotic interferon stimulated gene 54 (ISG54) in macrophages and IFN-γ in T cells. To investigate the IRF3-IFN-γ-ISG54 nexus, we injected C57Bl/6 (B6) and IRF3KO mice s.c. with luciferase-producing B16-F10 tumor cells. Tumor growth as measured by luciferase levels was similar between B6 and IRF3KO mice at days 2 and 6, but was significantly greater at day 9 in IRF3KO mice compared with B6 mice...
June 23, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28647346/sting-is-involved-in-antiviral-immune-response-against-vzv-infection-via-the-induction-of-type-i-and-iii-ifn-pathways
#13
Ji-Ae Kim, Seul-Ki Park, Seong-Wook Seo, Chan-Hee Lee, Ok Sarah Shin
Varicella Zoster Virus (VZV) is a human-restricted α-herpesvirus that exhibits tropism for the skin. The VZV host receptors and downstream signaling pathways responsible for the antiviral innate immune response in the skin are not completely understood. Here, we show that stimulator of interferon genes (STING) mediates an important host defense against VZV infection in dermal cells including human dermal fibroblasts (HDFs) and HaCaT keratinocytes. Inhibition of STING using small interfering RNA (siRNA) or short hairpin RNA (shRNA)-mediated gene disruption resulted in enhanced viral replication but diminished IRF3 phosphorylation and induction of IFNs and pro-inflammatory cytokines...
June 21, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28634691/modulation-of-rotavirus-severe-gastroenteritis-by-the-combination-of-probiotics-and-prebiotics
#14
REVIEW
Guadalupe Gonzalez-Ochoa, Lilian K Flores-Mendoza, Ramona Icedo-Garcia, Ricardo Gomez-Flores, Patricia Tamez-Guerra
Annual mortality rates due to infectious diarrhea are about 2.2 million; children are the most vulnerable age group to severe gastroenteritis, representing group A rotaviruses as the main cause of disease. One of the main factors of rotavirus pathogenesis is the NSP4 protein, which has been characterized as a viral toxin involved in triggering several cellular responses leading to diarrhea. Furthermore, the rotavirus protein NSP1 has been associated with interferon production inhibition by inducing the degradation of interferon regulatory factors IRF3, IRF5, and IRF7...
June 20, 2017: Archives of Microbiology
https://www.readbyqxmd.com/read/28618271/lck-hck-fgr-mediated-tyrosine-phosphorylation-negatively-regulates-tbk1-to-restrain-innate-antiviral-responses
#15
Shengduo Liu, Shasha Chen, Xinran Li, Shiying Wu, Qian Zhang, Qiuheng Jin, Lin Hu, Ruyuan Zhou, Zhengyang Yu, Fansen Meng, Siwen Wang, Yaowei Huang, Sheng Ye, Li Shen, Zongping Xia, Jian Zou, Xin-Hua Feng, Pinglong Xu
Cytosolic nucleic acid sensing elicits interferon production for primary antiviral defense through cascades controlled by protein ubiquitination and Ser/Thr phosphorylation. Here we show that TBK1, a core kinase of antiviral pathways, is inhibited by tyrosine phosphorylation. The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. Accordingly, antiviral sensing and resistance were substantially enhanced in Lck/Hck/Fgr triple knockout cells and ectopic expression of Lck/Hck/Fgr dampened the antiviral defense in cells and zebrafish...
June 14, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28604814/functional-paralysis-of-gm-csf-derived-bone-marrow-cells-productively-infected-with-ectromelia-virus
#16
Lidia Szulc-Dąbrowska, Justyna Struzik, Agnieszka Ostrowska, Maciej Guzera, Felix N Toka, Magdalena Bossowska-Nowicka, Małgorzata M Gieryńska, Anna Winnicka, Zuzanna Nowak, Marek G Niemiałtowski
Ectromelia virus (ECTV) is an orthopoxvirus responsible for mousepox, a lethal disease of certain strains of mice that is similar to smallpox in humans, caused by variola virus (VARV). ECTV, similar to VARV, exhibits a narrow host range and has co-evolved with its natural host. Consequently, ECTV employs sophisticated and host-specific strategies to control the immune cells that are important for induction of antiviral immune response. In the present study we investigated the influence of ECTV infection on immune functions of murine GM-CSF-derived bone marrow cells (GM-BM), comprised of conventional dendritic cells (cDCs) and macrophages...
2017: PloS One
https://www.readbyqxmd.com/read/28603526/ftr83-a-member-of-the-large-fish-specific-fintrim-family-triggers-ifn-pathway-and-counters-viral-infection
#17
Christelle Langevin, Elina Aleksejeva, Armel Houel, Valérie Briolat, Corinne Torhy, Aurélie Lunazzi, Jean-Pierre Levraud, Pierre Boudinot
Tripartite motif (TRIM) proteins are involved in various cellular functions and constitute key factors of the antiviral innate immune response. TRIM proteins can bind viral particles directly, sending them to degradation by the proteasome, or ubiquitinate signaling molecules leading to upregulation of innate immunity. TRIM proteins are present in across metazoans but are particularly numerous in vertebrates where genes comprising a B30.2 domain have been often duplicated. In fish, a TRIM subset named finTRIM is highly diversified, with large gene numbers and clear signatures of positive selection in the B30...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28602740/protective-immunity-against-rock-bream-iridovirus-rbiv-infection-and-tlr3-mediated-type-i-interferon-signaling-pathway-in-rock-bream-oplegnathus-fasciatus-following-poly-i-c-administration
#18
Myung-Hwa Jung, Sung-Ju Jung
In this study, we evaluated the potential of poly (I:C) to induce antiviral status for protecting rock bream from RBIV infection. Rock bream injected with poly (I:C) at 2 days before infection (1.1 × 10(4)) at 20 °C had significantly higher protection with RPS 13.4% and 33.4% at 100 and 200 μg/fish, respectively, through 100 days post infection (dpi). The addition of boost immunization with poly (I:C) at before/post infection at 20 °C clearly enhanced the level of protection showing 33.4% and 60.0% at 100 and 200 μg/fish, respectively...
August 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28600291/sphingosine-1-phosphate-lyase-enhances-the-activation-of-ikk%C3%AE%C2%B5-to-promote-type-i-ifn-mediated-innate-immune-responses-to-influenza-a-virus-infection
#19
Madhuvanthi Vijayan, Chuan Xia, Yul Eum Song, Hanh Ngo, Caleb J Studstill, Kelly Drews, Todd E Fox, Marc C Johnson, John Hiscott, Mark Kester, Stephen Alexander, Bumsuk Hahm
Sphingosine 1-phosphate (S1P) lyase (SPL) is an intracellular enzyme that mediates the irreversible degradation of the bioactive lipid S1P. We have previously reported that overexpressed SPL displays anti-influenza viral activity; however, the underlying mechanism is incompletely understood. In this study, we demonstrate that SPL functions as a positive regulator of IKKε to propel type I IFN-mediated innate immune responses against viral infection. Exogenous SPL expression inhibited influenza A virus replication, which correlated with an increase in type I IFN production and IFN-stimulated gene accumulation upon infection...
June 9, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28595092/ebolavirus-protein-vp24-interferes-with-innate-immune-responses-by-inhibiting-interferon-%C3%AE-1-gene-expression
#20
Felix He, Krister Melén, Sari Maljanen, Rickard Lundberg, Miao Jiang, Pamela Österlund, Laura Kakkola, Ilkka Julkunen
Ebolaviruses (EBOV) cause severe disease with a recent outbreak in West Africa in 2014-2015 leading to more than 28 000 cases and 11 300 fatalities. This emphasizes the urgent need for better knowledge on these highly pathogenic RNA viruses. Host innate immune responses play a key role in restricting the spread of a viral disease. In this study we systematically analyzed the effects of cloned EBOV genes on the main host immune response to RNA viruses: the activation of RIG-I pathway and type I and III interferon (IFN) gene expression...
June 5, 2017: Virology
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