title: The GOLD domain-containing protein TMED7 inhibits TLR4 signalling from the endosome upon LPS stimulation.
abstract: Toll-like receptor 4 is an innate immune receptor responsible for the recognition of the Gram-negative cell wall component lipopolysaccharide. Here we show that transmembrane emp24 domain-containing protein 7 (TMED7) inhibits MyD88-independent toll-like receptor 4 signalling. TMED7 overexpression inhibits the ability of TRAM, an adaptor utilized by toll-like receptor 4, or lipopolysaccharide to activate the interferon regulatory factor 3-signalling pathway, whereas TMED7 knockdown enhances production of the cytokine, RANTES, following lipopolysaccharide stimulation. Upon lipopolysaccharide stimulation, TMED7 co-localizes with TRAM and toll-like receptor 4 in late endosomes where it encounters the negative regulator of TRAM, TAG. The TMED7 sequence is found in TAG because of a read-through from the tmed7 gene into the ticam2 gene. TMED7 is essential for TAG-mediated disruption of the TRAM/TRIF complex and the degradation of toll-like receptor 4. A TMED homologue, logjam, has a negative role in the Toll and IMD pathways in Drosophila melanogaster; therefore, TMEDs may have a conserved role in the regulation of innate immunity.
authors.affiliation: Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Doyle
authors.forename: Harald
authors.initials: H
authors.lastname: Husebye
authors.forename: Dympna J
authors.initials: DJ
authors.lastname: Connolly
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.forename: Anne F
authors.initials: AF
authors.lastname: McGettrick
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; C480228:TICAM2 protein, human; C574004:TMED7 protein, human; D051197:Toll-Like Receptor 4; D033921:Vesicular Transport Proteins