title: The COP II adaptor protein TMED7 is required to initiate and mediate the delivery of TLR4 to the plasma membrane.
abstract: Toll-like receptor 4 (TLR4), the receptor for the bacterial product endotoxin, is subject to multiple points of regulation at the levels of signaling, biogenesis, and trafficking. Dysregulation of TLR4 signaling can cause serious inflammatory diseases, such as sepsis. We found that the p24 family protein TMED7 (transmembrane emp24 protein transport domain containing 7) is required for the trafficking of TLR4 from the endoplasmic reticulum to the cell surface through the Golgi. TMED7 formed a stable complex with the ectodomain of TLR4, an interaction that required the coiled-coil and Golgi dynamics (GOLD) domains, but not the cytosolic, coat protein complex II (COP II) sorting motif, of TMED7. Depletion of TMED7 reduced TLR4 signaling mediated by the adaptor protein MyD88 (myeloid differentiation marker 88), but not that mediated by the adaptor proteins TRIF [Toll-interleukin-1 receptor (TIR) domain-containing adaptor protein inducing interferon-β] and TRAM (TRIF-related adaptor molecule). Truncated forms of TMED7 lacking the COP II sorting motif or the transmembrane domain were mislocalized and resulted in ligand-independent signaling that probably arises from receptors accumulated intracellularly. Together, these results support the hypothesis that p24 proteins perform a quality control step by recognizing correctly folded anterograde cargo, such as TLR4, in early secretory compartments and facilitating the translocation of this cargo to the cell surface.
authors: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
authors: Ardiyanto
authors: A
authors: Liaunardy-Jopeace
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors: Clare E
authors: CE
authors: Bryant
authors: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. njg11@cam.ac.uk.
authors: Nicholas J
authors: NJ
authors: Gay
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005434:Flow Cytometry; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D008024:Ligands; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D016296:Mutagenesis; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D008024:Ligands; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; C574004:TMED7 protein, human; D051197:Toll-Like Receptor 4; D033921:Vesicular Transport Proteins