TLR9 signals after translocating from the ER to CpG DNA in the lysosome

Eicke Latz; Annett Schoenemeyer; Alberto Visintin; Katherine A Fitzgerald; Brian G Monks; Cathrine F Knetter; Egil Lien; Nadra J Nilsen; Terje Espevik; Douglas T Golenbock

doi:10.1038/ni1028

TLR9 signals after translocating from the ER to CpG DNA in the lysosome

Nat Immunol. 2004 Feb;5(2):190-8. doi: 10.1038/ni1028. Epub 2004 Jan 11.

Authors

Eicke Latz¹, Annett Schoenemeyer, Alberto Visintin, Katherine A Fitzgerald, Brian G Monks, Cathrine F Knetter, Egil Lien, Nadra J Nilsen, Terje Espevik, Douglas T Golenbock

Affiliation

¹ Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Lazare Research Building 308, 364 Plantation Street, Worcester, MA 01605, USA.

PMID: 14716310
DOI: 10.1038/ni1028

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Antigens, Differentiation / genetics
Antigens, Differentiation / immunology
Biological Transport, Active
Cell Line
CpG Islands / immunology*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / immunology*
Dendritic Cells / immunology
Endoplasmic Reticulum / immunology*
Humans
In Vitro Techniques
Luminescent Proteins / genetics
Luminescent Proteins / immunology
Lysosomes / immunology*
Membrane Glycoproteins / genetics
Membrane Glycoproteins / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88
Receptors, Cell Surface / genetics
Receptors, Cell Surface / immunology*
Receptors, Immunologic / deficiency
Receptors, Immunologic / genetics
Receptors, Immunologic / immunology
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / immunology
Signal Transduction
Toll-Like Receptor 9
Toll-Like Receptors

Substances

Adaptor Proteins, Signal Transducing
Antigens, Differentiation
DNA-Binding Proteins
Luminescent Proteins
MYD88 protein, human
Membrane Glycoproteins
Myd88 protein, mouse
Myeloid Differentiation Factor 88
Receptors, Cell Surface
Receptors, Immunologic
Recombinant Fusion Proteins
TLR9 protein, human
Tlr9 protein, mouse
Toll-Like Receptor 9
Toll-Like Receptors