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; Anne F McGettrick

doi:10.1038/ncomms1706

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.

Authors

Sarah L Doyle¹, Harald Husebye, Dympna J Connolly, Terje Espevik, Luke A J O'Neill, Anne F McGettrick

Affiliation

¹ Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.

PMID: 22426228
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