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

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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)

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.

Suggested Citation

  • Sarah L. Doyle & Harald Husebye & Dympna J. Connolly & Terje Espevik & Luke A.J. O'Neill & Anne F. McGettrick, 2012. "The GOLD domain-containing protein TMED7 inhibits TLR4 signalling from the endosome upon LPS stimulation," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1706
    DOI: 10.1038/ncomms1706
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    Cited by:

    1. Julia D. Knopf & Susanne S. Steigleder & Friederike Korn & Nathalie Kühnle & Marina Badenes & Marina Tauber & Sebastian J. Theobald & Jan Rybniker & Colin Adrain & Marius K. Lemberg, 2024. "RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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