DOCSLIB.ORG

Pattern Recognition Receptors Pattern Recognition Receptors Pattern Recognition Receptors (Prrs) Are Select Pattern Recognition Receptor Agonists

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Pattern Recognition Receptors Pattern Recognition Receptors Pattern recognition receptors (PRRs) are Select Pattern Recognition Receptor Agonists essential for detecting invading pathogens Toll-like Receptors (TLRs) C-type Lectin Receptors (CLRs) and initiating the innate and adaptive TLRs Agonist(s) Source CLRs Agonist(s) Source immune response. There are multiple TLR1/ Triacyl lipopeptides Bacteria BDCA-2 Mannose, fucose Unknown families of PRRs including the membrane- TLR2 CLEC-1 Unknown Unknown associated Toll-like receptors (TLRs) and TLR2 Lipoproteins Multiple Pathogens C-type lectin receptors (CLRs), and the CLEC-2 Unknown Endogenous podoplanin Peptidoglycan (PGN) Bacteria (PDPN); HIV; Snake venom cytosolic NOD-like receptors (NLRs), RIG-I- Porins Bacteria protein rhodocytin like receptors (RLRs), and AIM2-like Zymosan Fungi CLEC4D/ Unknown Unknown CLECSF8 receptors (ALRs). PRRs are activated by b-Glycan Fungi specific pathogen-associated molecular CLEC9a Filamentous form Necrotic cells GPI-mucin Protozoa of actin patterns (PAMPs) present in microbial Envelope glycoproteins Viruses CLEC12B Unknown Unknown molecules or by damage-associated TLR2/ Diacyl lipopeptides Bacteria DCAR/ Unknown Unknown molecular patterns (DAMPs) exposed on the TLR6 CLEC4B Lipoteichoic acid (LTA) Bacteria surface of, or released by, damaged cells. In DCIR/ Mannose, fucose HIV TLR3 Double-stranded RNA Viruses CLEC4A most cases, ligand recognition by PRRs Poly (I:C) Synthetic analog of DC-SIGN/ High mannose, Candida albicans, triggers intracellular signal transduction double-stranded RNA CD209 fucose Cytomegalovirus, Dengue virus, filoviruses, HIV, cascades that result in the expression of TLR4 Lipopolysaccharide (LPS) Bacteria Leishmania spp., measles pro-inflammatory cytokines, chemokines, Glycoinositol- Protozoa virus, Mycobacterium spp., 1 phospholipids SARS, Schistosoma mansoni and antiviral molecules. In contrast, egg antigen Envelope glycoproteins Viruses activation of some ALRs and NLRs leads to Dectin-1/ b-1,3 glucans Fungi, mycobacteria Host-derived HMGB1 and Endogenous CLEC7A the formation of multiprotein inflammasome HSPs complexes that serve as platforms for the Dectin-2/ High mannose; Aspergillus fumigatus, TLR5 Flagellin Bacteria CLEC6A a-mannans Candida albicans, 2 Cryptococcus neoformans, cleavage and activation of Caspase-1. TLR7 Single-stranded RNA Viruses Caspase-1 promotes the maturation and Histoplasma capsulatum, TLR8 Single-stranded RNA Viruses Microsporum audouinii, secretion of IL-1b and IL-18, which further Mycobacterium tuberculosis, TLR9 Unmethylated CpG DNA Bacteria Paracoccidioides brasiliensis, amplifies the pro-inflammatory immune Saccharomyces cerevisiae, Protozoa response. Since a single pathogen can Trichophyton rubrum Viruses simultaneously activate multiple PRRs, LOX-1/ Oxidized low Endogenous; Bacteria; Also Mitochondrial DNA Endogenous OLR1 density lipoprotein activated by aged cells, crosstalk between different receptors may (ox-LDL); modified advanced glycation end TLR10 Unknown Unknown lipoproteins products, and HSP70 also play a role in enhancing or inhibiting MDL-1/ Unknown Dengue virus 3 the immune response. Therefore, tight CLEC5A regulation of PRR signaling is required in RIG-I-like Receptors (RLRs) MICL/ Unknown Unknown order to eliminate infectious pathogens and RLRs Agonist(s) Source CLEC12A Mincle/ a-mannose, Candida albicans, Malassezia Short 5' triphosphate at the same time, prevent aberrant or CLEC4E glycolipids, spp., Mycobacterium RIG-I single-stranded RNA containing Viruses SAP130 tuberculosis, dead cells excessive PRR activation, which can lead to some double-stranded regions (endogenous) the development of inflammatory and MDA5 Long double-stranded RNA Viruses SIGNR3/ High mannose, Mycobacterium tuberculosis 4 autoimmune disorders. RNA CD209d fucose LGP2 Unknown Viruses References 1. Takeuchi, O. & S. Akira (2010) Cell 140: 805. 2. Schroder, K. & J. Tschopp (2010) Cell 140:821. 3. Kingeter, L.M. & X. Lin (2012) Cell. Mol. Immunol. 9:105. 4. Mogensen, T.H. (2009) Clin. Microbiol. Rev. 22:240. Cover Illustration: A model of the ligand-bound TLR1/TLR2 heterodimer based on the crystal structure [Adapted from Jin, M.S. et al. (2007) Cell 130:1071.] NOD-like Receptors (NLRs) NOD-like Receptors (NLRs) NLRs Agonist(s) Source NLRs Agonist(s) Source NOD1 (NLRC1) Meso-diaminopimelic acid (Meso-DAP) Bacteria NLRP3/NALP3 Adenoviral DNA; Bacterial RNA; Candida albicans/Saccharomyces cerevisiae; Damage signals: Extracellular ATP, NAD+, b-amyloid, and NOD2 (NLRC2) Muramyl dipeptide (MDP) Bacteria particulates such as calcium pyrophosphate dihydrate and CIITA Unknown monosodium urate; Pore-forming toxins: Hemolysins, Listeriolysin O, Nigericin, Pneumolysin; Xenogenous compounds: Silica, asbestos, NAIP Legionella pneumophila; Flagellin (Naip5) alum, and uric acid; Influenza and Sendai virus RNA; Lipopolysaccharide (LPS); Klebsiella pneumoniae, Mycobacterium NLRC3 Unknown tuberculosis, Salmonella typhimurium, Schistosoma mansoni NLRC4 (IPAF) Legionella pneumophila; Pseudomonas aeruginosa; Salmonella NLRP4-14/NALP4-14 Unknown typhimurium; Shigella flexneri NLRX1 Unknown NLRC5 Unknown NLRP1/NALP1 Bacillus anthracis lethal toxin; Muramyl dipeptide (MDP) NLRP2/NALP2 Unknown 2 Learn more | rndsystems.com/prr Toll-like Receptors Toll-like receptors (TLRs) are a family of type I transmembrane pattern recognition receptors (PRRs) that are expressed by a number of different immune and non-immune cell types including monocytes, macrophages, dendritic cells, neutrophils, B cells, T cells, fibroblasts, endothelial cells, and epithelial cells.1 TLRs initiate the immune response following recognition of either conserved, pathogen-associated molecular patterns (PAMPs) present in microbial molecules or damaged-associated molecular patterns (DAMPs) present in molecules released by damaged cells. There are ten functional TLRs in humans and twelve in mice.2 Of the human TLRs, TLR1, 2, 4, 5, 6, and 10 are expressed on the cell surface and primarily recognize microbial membrane and/or cell wall components, while TLR3, 7, 8, and 9 are expressed in the membranes of endolysosomal compartments and recognize nucleic acids.3 TLRs have a variable number of ligand-sensing, leucine-rich repeats at their N-terminal ends and a cytoplasmic Toll/IL-1 R (TIR) domain. The TIR domain mediates interactions between TLRs and adaptor proteins involved in regulating TLR signaling including MyD88, TRIF, TRAM, and TIRAP/MAL. Signaling pathways activated downstream of these adaptor molecules promote the expression of pro-inflammatory cytokines, chemokines, and type I and type III interferons. As a result, additional immune cells are recruited to the infection site and pathogenic microbes and infected cells are eliminated. Although TLRs provide protection against a wide variety of pathogens, inappropriate or unregulated activation of TLR signaling can lead to chronic inflammatory and autoimmune disorders.4 References 1. Iwasaki, A. & R. Medzhitov (2004) Nat. Immunol. 5:987. 3. Blasius, A.L. & B. Beutler (2010) Immunity 32:305. 2. Kawai, T. & S. Akira (2011) Immunity 34:637. 4. Midwood, K.S. et al. (2009) Curr. Drug Targets 10:1139. TLR2/TLR6 TLR1/TLR2 TLR5 TLR4 TLR10 CD14 CD14 CD36 TLR2 Antibody (µg/mL) 10-2 10-1 100 CD14 TIRAP TIRAP 0.7 0.6 MD-2 MyD88 TIRAP MyD88 MyD88 TRAM Secretion (Mean O.D.) IL-8 MyD88 MyD88 0.6 0.5 TRIF 0.5 0.4 Antibody Endosome Lipopeptide TLR7 0.4 0.3 RIP1 IRAK4 IRAK1/2 TLR8 TLR9 TLR3 IL-8 Secretion (Mean O.D.) Secretion IL-8 0.3 0.2 TRAF-6 TAB1/2 TAK1 TRAF-6 MyD88 MyD88 TRIF 0.2 0.1 MyD88 10-2 10-1 100 TRAF-3 TRAF-3 Pam CSK (µg/mL) TANK 3 4 TLR2 Ligand-induced IL-8 Secretion and Neutralization IKK IRF7 using an Anti-Human TLR2 Antibody. The HEK293 human embryonic kidney cell line transfected with human TLR2 MKK RIP1 TBK1 was treated with increasing concentrations of the synthetic IKKε Proteasome TAB1/2 tri-palmitoylated lipopeptide Pam3CSK4. IL-8 secretion was IRF7 Homodimer TAK1 TRAF-6 measured using the Human CXCL8/IL-8 Quantikine® ELISA TRAF-3 Kit (Catalog # D8000C; gray line). The stimulatory effect IκB TANK Proteasome induced by 0.5 μg/mL Pam3CSK4 was neutralized by IKK treating the cells with increasing concentrations of a IκB IRF3 Mouse Anti-Human TLR2 Monoclonal Antibody (Catalog # NFκB MAB2616; purple line). JNK IκB MKK 40 p38 TBK1 IKKε IκB NFκB 30 p38 JNK IRF7 IRF3 Homodimer IRF3 20 IRF7 Homodimer IRF3 Homodimer Relative Cell Number Cell Relative 40 Domain Key 0 0 1 2 3 4 Leucine-Rich Repeat 10 10 10 10 10 TLR7 Domain (LRR) IRF3 NFκB AP-1 IRF7 NFκB AP-1 IRF3 or IRF7 Toll/IL-1 Receptor Intracellular Detection of TLR7 by Flow Cytometry. The Domain (TIR) Pro-inflammatory Cytokines: Ramos human Burkitt’s lymphoma cell line was stained Death Domain (DD) IL-1β, TNF-α, IL-6, IL-8, IL-18 with a PE-conjugated Mouse Anti-Human TLR7 Monoclonal Kinase Domain Type I or Type III IFN & IFN-inducible genes © 2012 R&D Systems, Inc. Antibody (Catalog # IC5875P; filled histogram) or a PE- conjugated Mouse IgG2A Isotype Control (Catalog # IC003P; open histogram). Learn more | rndsystems.com/tlr 3 C-type Lectin Receptors C-type lectin receptors (CLRs) are a diverse family of soluble and transmembrane proteins that contain one or more C-type lectin-like domain (CTLD). Multiple members of the CLR family are considered to be pattern recognition receptors (PRRs) due to their ability to recognize pathogen- associated molecules and induce intracellular signaling pathways that regulate the immune response. With the exception of DC-SIGN,
Recommended publications
  • Inflammasome Activation-Induced Hypercoagulopathy

    Inflammasome Activation-Induced Hypercoagulopathy

    cells Review Inflammasome Activation-Induced Hypercoagulopathy: Impact on Cardiovascular Dysfunction Triggered in COVID-19 Patients Lealem Gedefaw, Sami Ullah, Polly H. M. Leung , Yin Cai, Shea-Ping Yip * and Chien-Ling Huang * Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China; [email protected] (L.G.); [email protected] (S.U.); [email protected] (P.H.M.L.); [email protected] (Y.C.) * Correspondence: [email protected] (S.-P.Y.); [email protected] (C.-L.H.) Abstract: Coronavirus disease 2019 (COVID-19) is the most devastating infectious disease in the 21st century with more than 2 million lives lost in less than a year. The activation of inflammasome in the host infected by SARS-CoV-2 is highly related to cytokine storm and hypercoagulopathy, which significantly contribute to the poor prognosis of COVID-19 patients. Even though many studies have shown the host defense mechanism induced by inflammasome against various viral infections, mechanistic interactions leading to downstream cellular responses and pathogenesis in COVID-19 remain unclear. The SARS-CoV-2 infection has been associated with numerous cardiovascular disor- ders including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The inflammatory response triggered by the activation of NLRP3 inflammasome under certain car- diovascular conditions resulted in hyperinflammation or the modulation of angiotensin-converting enzyme 2 signaling pathways. Perturbations of several target cells and tissues have been described in inflammasome activation, including pneumocytes, macrophages, endothelial cells, and dendritic cells. Citation: Gedefaw, L.; Ullah, S.; Leung, P.H.M.; Cai, Y.; Yip, S.-P.; The interplay between inflammasome activation and hypercoagulopathy in COVID-19 patients is an Huang, C.-L.
  • NLRP6 Induces Pyroptosis by Activation of Caspase-1 in Gingival

    NLRP6 Induces Pyroptosis by Activation of Caspase-1 in Gingival

    JDRXXX10.1177/0022034518775036Journal of Dental ResearchNLRP6 Induces Pyroptosis 775036research-article2018 Research Reports: Biological Journal of Dental Research 2018, Vol. 97(12) 1391 –1398 © International & American Associations NLRP6 Induces Pyroptosis by Activation for Dental Research 2018 Article reuse guidelines: of Caspase-1 in Gingival Fibroblasts sagepub.com/journals-permissions DOI:https://doi.org/10.1177/0022034518775036 10.1177/0022034518775036 journals.sagepub.com/home/jdr W. Liu1* , J. Liu1*, W. Wang1, Y. Wang2,3, and X. Ouyang1 Abstract NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, has been reported to participate in inflammasome formation. Activation of inflammasome triggers a caspase-1–dependent programming cell death called pyroptosis. However, whether NLRP6 induces pyroptosis has not been investigated. In this study, we showed that NLRP6 overexpression activated caspase-1 and gasdermin-D and then induced pyroptosis of human gingival fibroblasts, resulting in release of proinflammatory mediators interleukin (IL)–1β and IL-18. Moreover, NLRP6 was highly expressed in gingival tissue of periodontitis compared with healthy controls. Porphyromonas gingivalis, which is a commensal bacterium and has periodontopathic potential, induced pyroptosis of gingival fibroblasts by activation of NLRP6. Together, we, for the first time, identified that NLRP6 could induce pyroptosis of gingival fibroblasts by activation of caspase-1 and may play a role in periodontitis. Keywords: periodontitis, pattern recognition receptors, cell death, Porphyromonas gingivalis, inflammasomes, flow cytometry Introduction have been demonstrated to participate in periodontitis (Huang et al. 2015; Chaves de Souza et al. 2016; Marchesan et al. Pyroptosis is a newly identified type of programmed cell death 2016).
  • Podoplanin Regulates Mammary Stem Cell Function and Tumorigenesis by Potentiating Wnt/Β-Catenin Signaling Laura Bresson1,2,3, Marisa M

    Podoplanin Regulates Mammary Stem Cell Function and Tumorigenesis by Potentiating Wnt/Β-Catenin Signaling Laura Bresson1,2,3, Marisa M

    © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev160382. doi:10.1242/dev.160382 STEM CELLS AND REGENERATION RESEARCH ARTICLE Podoplanin regulates mammary stem cell function and tumorigenesis by potentiating Wnt/β-catenin signaling Laura Bresson1,2,3, Marisa M. Faraldo1,4, Amandine Di-Cicco1, Miguel Quintanilla5, Marina A. Glukhova1,4 and Marie-Ange Deugnier1,4,* ABSTRACT K5/14), P-cadherin, smooth muscle-specific contractile proteins, Δ Stem cells (SCs) drive mammary development, giving rise postnatally and the transcription factors Np63 (an isoform of Trp63) and Slug/ to an epithelial bilayer composed of luminal and basal myoepithelial Snail2, which are essential for the maintenance of basal cell identity cells. Dysregulation of SCs is thought to be at the origin of certain breast (Yalcin-Ozuysal et al., 2010; Guo et al., 2012). The luminal cell cancers; however, the molecular identity of SCs and the factors layer is characterized by the expression of K8/18. It includes a regulating their function remain poorly defined. We identified the subset of hormone-sensing cells that express estrogen, progesterone transmembrane protein podoplanin (Pdpn) as a specific marker of the and prolactin receptors (ER, PR and PrlR, respectively) and produce basal compartment, including multipotent SCs, and found Pdpn local mediators involved in the paracrine control of basal and localized at the basal-luminal interface. Embryonic deletion of Pdpn luminal cell function (Brisken and Ataca, 2015). targeted to basal cells diminished basal and luminal SC activity and It is established that both mammary lineages, basal and luminal, affected the expression of several Wnt/β-catenin signaling components originate from a common embryonic stem cell (SC) expressing basal in basal cells.
  • Scholarly Commons NLRX1 Modulates Differentially NLRP3

    Scholarly Commons NLRX1 Modulates Differentially NLRP3

    University of the Pacific Scholarly Commons Dugoni School of Dentistry Faculty Articles Arthur A. Dugoni School of Dentistry 10-1-2018 NLRX1 modulates differentially NLRP3 inflammasome activation and NF-κB signaling during Fusobacterium nucleatum infection Shu Chen Hung University of the Pacific Arthur A. Dugoni School of Dentistry Pei Rong Huang Chang Gung University Cassio Luiz Coutinho Almeida-Da-Silva University of the Pacific Arthur A. Dugoni School of Dentistry, [email protected] Kalina R. Atanasova University of Florida Ozlem Yilmaz Medical University of South Carolina See next page for additional authors Follow this and additional works at: https://scholarlycommons.pacific.edu/dugoni-facarticles Part of the Dentistry Commons Recommended Citation Hung, S., Huang, P., Almeida-Da-Silva, C. L., Atanasova, K. R., Yilmaz, O., & Ojcius, D. M. (2018). NLRX1 modulates differentially NLRP3 inflammasome activation and NF-κB signaling during Fusobacterium nucleatum infection. Microbes and Infection, 20(9-10), 615–625. DOI: 10.1016/j.micinf.2017.09.014 https://scholarlycommons.pacific.edu/dugoni-facarticles/705 This Article is brought to you for free and open access by the Arthur A. Dugoni School of Dentistry at Scholarly Commons. It has been accepted for inclusion in Dugoni School of Dentistry Faculty Articles by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. Authors Shu Chen Hung, Pei Rong Huang, Cassio Luiz Coutinho Almeida-Da-Silva, Kalina R. Atanasova, Ozlem Yilmaz, and David M. Ojcius This article is available at Scholarly Commons: https://scholarlycommons.pacific.edu/dugoni-facarticles/705 Version of Record: https://www.sciencedirect.com/science/article/pii/S1286457917301582 Manuscript_dd7f93413c97aff4865d54242a8b21e7 1 NLRX1 modulates differentially NLRP3 inflammasome activation 2 and NF-κB signaling during Fusobacterium nucleatum infection 3 4 5 Shu-Chen Hung 1, *, Pei-Rong Huang 2, Cássio Luiz Coutinho Almeida-da-Silva 1,3 , 6 Kalina R.
  • The Intestinal Parasite Cryptosporidium Is Controlled by an Enterocyte Intrinsic Inflammasome That Depends on NLRP6

    The Intestinal Parasite Cryptosporidium Is Controlled by an Enterocyte Intrinsic Inflammasome That Depends on NLRP6

    The intestinal parasite Cryptosporidium is controlled by an enterocyte intrinsic inflammasome that depends on NLRP6 Adam Saterialea,1, Jodi A. Gullicksruda, Julie B. Engilesa, Briana I. McLeoda, Emily M. Kuglera, Jorge Henao-Mejiab,c, Ting Zhoud, Aaron M. Ringd, Igor E. Brodskya, Christopher A. Huntera, and Boris Striepena,2 aDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; bDepartment of Pathology and Laboratory Medicine, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; cDivision of Protective Immunity, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104; and dDepartment of Immunology, Yale School of Medicine, Yale University, New Haven, CT 06519 Edited by Stephen M. Beverley, Washington University School of Medicine, St. Louis, MO, and approved December 1, 2020 (received for review April 24, 2020) The apicomplexan parasite Cryptosporidium infects the intestinal Murine infection with C. tyzzeri resembles human cryptospo- epithelium. While infection is widespread around the world, chil- ridiosis in location, pathology, and resolution and provides an dren in resource-poor settings suffer a disproportionate disease important tool to define the host and parasite factors that burden. Cryptosporidiosis is a leading cause of diarrheal disease, determine the outcome of infection and to identify the im- responsible for mortality and stunted growth in children. CD4 mune
  • CD56+ T-Cells in Relation to Cytomegalovirus in Healthy Subjects and Kidney Transplant Patients

    CD56+ T-Cells in Relation to Cytomegalovirus in Healthy Subjects and Kidney Transplant Patients

    CD56+ T-cells in Relation to Cytomegalovirus in Healthy Subjects and Kidney Transplant Patients Institute of Infection and Global Health Department of Clinical Infection, Microbiology and Immunology Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy by Mazen Mohammed Almehmadi December 2014 - 1 - Abstract Human T cells expressing CD56 are capable of tumour cell lysis following activation with interleukin-2 but their role in viral immunity has been less well studied. The work described in this thesis aimed to investigate CD56+ T-cells in relation to cytomegalovirus infection in healthy subjects and kidney transplant patients (KTPs). Proportions of CD56+ T cells were found to be highly significantly increased in healthy cytomegalovirus-seropositive (CMV+) compared to cytomegalovirus-seronegative (CMV-) subjects (8.38% ± 0.33 versus 3.29%± 0.33; P < 0.0001). In donor CMV-/recipient CMV- (D-/R-)- KTPs levels of CD56+ T cells were 1.9% ±0.35 versus 5.42% ±1.01 in D+/R- patients and 5.11% ±0.69 in R+ patients (P 0.0247 and < 0.0001 respectively). CD56+ T cells in both healthy CMV+ subjects and KTPs expressed markers of effector memory- RA T-cells (TEMRA) while in healthy CMV- subjects and D-/R- KTPs the phenotype was predominantly that of naïve T-cells. Other surface markers, CD8, CD4, CD58, CD57, CD94 and NKG2C were expressed by a significantly higher proportion of CD56+ T-cells in healthy CMV+ than CMV- subjects. Functional studies showed levels of pro-inflammatory cytokines IFN-γ and TNF-α, as well as granzyme B and CD107a were significantly higher in CD56+ T-cells from CMV+ than CMV- subjects following stimulation with CMV antigens.
  • Post-Transcriptional Inhibition of Luciferase Reporter Assays

    Post-Transcriptional Inhibition of Luciferase Reporter Assays

    THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 34, pp. 28705–28716, August 17, 2012 © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Post-transcriptional Inhibition of Luciferase Reporter Assays by the Nod-like Receptor Proteins NLRX1 and NLRC3* Received for publication, December 12, 2011, and in revised form, June 18, 2012 Published, JBC Papers in Press, June 20, 2012, DOI 10.1074/jbc.M111.333146 Arthur Ling‡1,2, Fraser Soares‡1,2, David O. Croitoru‡1,3, Ivan Tattoli‡§, Leticia A. M. Carneiro‡4, Michele Boniotto¶, Szilvia Benko‡5, Dana J. Philpott§, and Stephen E. Girardin‡6 From the Departments of ‡Laboratory Medicine and Pathobiology and §Immunology, University of Toronto, Toronto M6G 2T6, Canada, and the ¶Modulation of Innate Immune Response, INSERM U1012, Paris South University School of Medicine, 63, rue Gabriel Peri, 94276 Le Kremlin-Bicêtre, France Background: A number of Nod-like receptors (NLRs) have been shown to inhibit signal transduction pathways using luciferase reporter assays (LRAs). Results: Overexpression of NLRX1 and NLRC3 results in nonspecific post-transcriptional inhibition of LRAs. Conclusion: LRAs are not a reliable technique to assess the inhibitory function of NLRs. Downloaded from Significance: The inhibitory role of NLRs on specific signal transduction pathways needs to be reevaluated. Luciferase reporter assays (LRAs) are widely used to assess the Nod-like receptors (NLRs)7 represent an important class of activity of specific signal transduction pathways. Although pow- intracellular pattern recognition molecules (PRMs), which are erful, rapid and convenient, this technique can also generate implicated in the detection and response to microbe- and dan- www.jbc.org artifactual results, as revealed for instance in the case of high ger-associated molecular patterns (MAMPs and DAMPs), throughput screens of inhibitory molecules.
  • NOD-Like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy

    NOD-Like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy

    International Journal of Molecular Sciences Review NOD-like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy Rayne R. Lim 1,2,3, Margaret E. Wieser 1, Rama R. Ganga 4, Veluchamy A. Barathi 5, Rajamani Lakshminarayanan 5 , Rajiv R. Mohan 1,2,3,6, Dean P. Hainsworth 6 and Shyam S. Chaurasia 1,2,3,* 1 Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; [email protected] (R.R.L.); [email protected] (M.E.W.); [email protected] (R.R.M.) 2 Department of Biomedical Sciences, University of Missouri, Columbia, MO 652011, USA 3 Ophthalmology, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 652011, USA 4 Surgery, University of Missouri, Columbia, MO 652011, USA; [email protected] 5 Singapore Eye Research Institute, Singapore 169856, Singapore; [email protected] (V.A.B.); [email protected] (R.L.) 6 Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 652011, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-573-882-3207 Received: 9 December 2019; Accepted: 27 January 2020; Published: 30 January 2020 Abstract: Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression.
  • Identification and Expression of the Laboratory of Genetics and Physiology 2 Gene in Common Carp Cyprinus Carpio

    Identification and Expression of the Laboratory of Genetics and Physiology 2 Gene in Common Carp Cyprinus Carpio

    Journal of Fish Biology (2014) doi:10.1111/jfb.12541, available online at wileyonlinelibrary.com Identification and expression of the laboratory of genetics and physiology 2 gene in common carp Cyprinus carpio X. L. Cao*†, J. J. Chen†,Y.Cao†,G.X.Nie†,Q.Y.Wan*,L.F.Wang† and J. G. Su*‡ *College of Animal Science and Technology, Northwest A&F University, Yangling 712100, People’s Republic of China and †College of Fisheries, Henan Normal University, Xinxiang 453007, People’s Republic of China (Received 29 April 2014, Accepted 9 September 2014) In this study, a laboratory of genetics and physiology 2 gene (lgp2) from common carp Cyprinus car- pio was isolated and characterized. The full-length complementary (c)DNA of lgp2 was 3061 bp and encoded a polypeptide of 680 amino acids, with an estimated molecular mass of 77 341⋅2Daanda predicted isoelectric point of 6⋅53. The predicted protein included four main overlapping structural domains: a conserved restriction domain of bacterial type III restriction enzyme, a DEAD–DEAH box helicase domain, a helicase super family C-terminal domain and a regulatory domain. Real-time quantitative polymerase chain reaction (PCR) showed widespread expression of lgp2, mitochondrial antiviral signalling protein (mavs) and interferon transcription factor 3 (irf3) in tissues of nine organs. lgp2, mavs and irf3 expression levels were significantly induced in all examined organs by infec- tion with koi herpesvirus (KHV). lgp2, mavs and irf3 messenger (m)RNA levels were significantly up-regulated in vivo after KHV infection, and lgp2 transcripts were also significantly enhanced in vitro after stimulation with synthetic, double-stranded RNA polyinosinic polycytidylic [poly(I:C)].
  • Integrative Genome Analysis of Somatic P53 Mutant Osteosarcomas Identifies Ets2-Dependent Regulation of Small Nucleolar Rnas by Mutant P53 Protein

    Integrative Genome Analysis of Somatic P53 Mutant Osteosarcomas Identifies Ets2-Dependent Regulation of Small Nucleolar Rnas by Mutant P53 Protein

    Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Integrative genome analysis of somatic p53 mutant osteosarcomas identifies Ets2-dependent regulation of small nucleolar RNAs by mutant p53 protein Rasoul Pourebrahim,1 Yun Zhang,1 Bin Liu,1 Ruli Gao,1 Shunbin Xiong,1 Patrick P. Lin,2 Mark J. McArthur,3 Michael C. Ostrowski,4 and Guillermina Lozano1 1Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 2Department of Orthopedic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 3Department of Veterinary Medicine and Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 4Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA TP53 is the most frequently mutated gene in human cancer. Many mutant p53 proteins exert oncogenic gain-of- function (GOF) properties that contribute to metastasis, but the mechanisms mediating these functions remain poorly defined in vivo. To elucidate how mutant p53 GOF drives metastasis, we developed a traceable somatic os- teosarcoma mouse model that is initiated with either a single p53 mutation (p53R172H) or p53 loss in osteoblasts. Our study confirmed that p53 mutant mice developed osteosarcomas with increased metastasis as compared with p53-null mice. Comprehensive transcriptome RNA sequencing (RNA-seq) analysis of 16 tumors identified a cluster of small nucleolar RNAs (snoRNAs) that are highly up-regulated in p53 mutant tumors. Regulatory element analysis of these deregulated snoRNA genes identified strong enrichment of a common Ets2 transcription factor-binding site. Homozygous deletion of Ets2 in p53 mutant mice resulted in strong down-regulation of snoRNAs and reversed the prometastatic phenotype of mutant p53 but had no effect on osteosarcoma development, which remained 100% penetrant.
  • Mapping the Genetic Architecture of Gene Regulation in Whole Blood

    Mapping the Genetic Architecture of Gene Regulation in Whole Blood

    Mapping the Genetic Architecture of Gene Regulation in Whole Blood Katharina Schramm1,2., Carola Marzi3,4,5., Claudia Schurmann6., Maren Carstensen7,8., Eva Reinmaa9,10, Reiner Biffar11, Gertrud Eckstein1, Christian Gieger12, Hans-Jo¨ rgen Grabe13, Georg Homuth6, Gabriele Kastenmu¨ ller14, Reedik Ma¨gi10, Andres Metspalu9,10, Evelin Mihailov10,15, Annette Peters2, Astrid Petersmann16, Michael Roden7,8,17, Konstantin Strauch12,18, Karsten Suhre14,19, Alexander Teumer6,UweVo¨ lker6, Henry Vo¨ lzke20, Rui Wang-Sattler3,4, Melanie Waldenberger3,4, Thomas Meitinger1,2,21, Thomas Illig22, Christian Herder7,8., Harald Grallert3,4,5., Holger Prokisch1,2*. 1 Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany, 2 Institute of Human Genetics, Technical University Munich, Mu¨nchen, Germany, 3 Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany, 4 Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany, 5 German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany, 6 Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany, 7 Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Du¨sseldorf, Du¨sseldorf, Germany, 8 German Center for Diabetes Research (DZD e.V.),
  • Pattern Recognition Receptors in Health and Diseases

    Pattern Recognition Receptors in Health and Diseases

    Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Pattern recognition receptors in health and diseases Danyang Li1,2 and Minghua Wu1,2 Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.