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

Nat Commun. 2012 Feb 28;3:707. doi: 10.1038/ncomms1706.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Cell Line
  • Chemokine CCL5 / biosynthesis
  • Endosomes / metabolism*
  • HEK293 Cells
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Lipopolysaccharides / immunology
  • Membrane Glycoproteins / metabolism
  • Myeloid Differentiation Factor 88 / metabolism
  • Protein Structure, Tertiary
  • Protein Transport
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Transfection
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • CCL5 protein, human
  • Chemokine CCL5
  • Interferon Regulatory Factor-3
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Myeloid Differentiation Factor 88
  • RNA, Small Interfering
  • TICAM1 protein, human
  • TICAM2 protein, human
  • TMED7 protein, human
  • Toll-Like Receptor 4
  • Vesicular Transport Proteins