The GOLD domain-containing protein TMED7 inhibits TLR4 signalling from the endosome upon LPS stimulation

Sarah L. Doyle, Harald Husebye, Dympna J. Connolly, Terje Espevik, Luke A.J. O'Neill and Anne F. McGettrick ()
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Sarah L. Doyle: Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin
Harald Husebye: Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology
Dympna J. Connolly: Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin
Terje Espevik: Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology
Luke A.J. O'Neill: Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin
Anne F. McGettrick: Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1706

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