Nature Immunology5, 190 - 198 (2004)
Published online: 11 January 2004; | doi:10.1038/ni1028
TLR9 signals after translocating from the ER to CpG DNA in the lysosome
Eicke Latz1, Annett Schoenemeyer1, Alberto Visintin1, Katherine A Fitzgerald1, Brian G Monks1, Cathrine F Knetter1, 2, Egil Lien1, Nadra J Nilsen2, Terje Espevik2, 3
& Douglas T Golenbock1, 3
1
University of Massachusetts Medical School, Division of Infectious Diseases and Immunology, 364 Plantation Street, Lazare Research Building 308, Worcester, Massachusetts 01605, USA.
2
Norwegian University of Science and Technology, Institute of Cancer Research and Molecular Medicine, Olav Kyrres gt. 3, N-7489 Trondheim, Norway.
Microbial DNA sequences containing unmethylated CpG dinucleotides activate Toll-like receptor 9 (TLR9). We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. Because there is no precedent for immune receptor signaling in the ER, we investigated how TLR9 is activated. We show that CpG DNA binds directly to TLR9 in ligand-binding studies. CpG DNA moves into early endosomes and is subsequently transported to a tubular lysosomal compartment. Concurrent with the movement of CpG DNA in cells, TLR9 redistributes from the ER to CpG DNA−containing structures, which also accumulate MyD88. Our data indicate a previously unknown mechanism of cellular activation involving the recruitment of TLR9 from the ER to sites of CpG DNA uptake, where signal transduction is initiated.
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