PloS one, 2018-10, Vol.13 (10), p.e0205303-e0205303
2018
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Details
- Autor(en) / Beteiligte
- Titel
- GPR108, an NF-κB activator suppressed by TIRAP, negatively regulates TLR-triggered immune responses
- Ist Teil von
- PloS one, 2018-10, Vol.13 (10), p.e0205303-e0205303
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Higher vertebrates have evolved innate and adaptive immune systems to defend against foreign substances and pathogens. Sophisticated regulatory circuits are needed to avoid inappropriate immune responses and inflammation. GPR108 is a seven-transmembrane family protein that activates NF-κB strongly when overexpressed. Surprisingly, its action in a physiological context is that of an antagonist of Toll-like receptor (TLR)-mediated signaling. Cells from Gpr108-null mice exhibit enhanced cytokine secretion and NF-κB and IRF3 signaling, whereas Gpr108-null macrophages reconstituted with GPR108 exhibit blunted signaling. Co-expression of TLRs and GPR108 reduces NF-κB and IFNβ promoter activation compared to expression of either TLRs or GPR108 alone. Upon TLR stimulation GPR108 abundance increases and the protein engages TLRs and their partners to reduce MyD88 expression and interfere with its binding to TLR4 through blocking MyD88 ubiquitination. In turn GPR108 is antagonized by TIRAP, an adaptor protein for TLR and MyD88. The interrelationships between GPR108 and innate immune signaling components are multifactorial and point to a membrane-associated signaling structure of significant complexity.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0205303Titel-ID: cdi_plos_journals_2121470029
- Format
- –
- Schlagworte
- Adaptive systems, Animals, Biology, Biology and Life Sciences, Cloning, CRISPR, Cytokines, Fibroblasts, Gene Expression Regulation, Genes, Reporter, Genomes, Green Fluorescent Proteins - genetics, Green Fluorescent Proteins - immunology, HEK293 Cells, Humans, Immune response, Immune system, Immunity, Innate, Immunology, Interferon regulatory factor 3, Kinases, Laboratories, Lipopolysaccharides - pharmacology, Luminescent Proteins - genetics, Luminescent Proteins - immunology, Macrophages, Medical schools, Medicine, Medicine and Health Sciences, Membrane Glycoproteins - genetics, Membrane Glycoproteins - immunology, Mice, Mice, Knockout, MyD88 protein, Myeloid Differentiation Factor 88 - genetics, Myeloid Differentiation Factor 88 - immunology, NF-kappa B - genetics, NF-kappa B - immunology, NF-κB protein, Proteins, Receptors, G-Protein-Coupled - deficiency, Receptors, G-Protein-Coupled - genetics, Receptors, G-Protein-Coupled - immunology, Receptors, Interleukin-1 - genetics, Receptors, Interleukin-1 - immunology, Red Fluorescent Protein, Research and Analysis Methods, Signal Transduction, Signaling, Stem cells, THP-1 Cells, TLR4 protein, Toll-Like Receptor 3 - genetics, Toll-Like Receptor 3 - immunology, Toll-Like Receptor 4 - genetics, Toll-Like Receptor 4 - immunology, Toll-Like Receptor 7 - genetics, Toll-Like Receptor 7 - immunology, Toll-Like Receptor 9 - genetics, Toll-Like Receptor 9 - immunology, Toll-like receptors, Ubiquitination, Vertebrates