TLR9 signals after translocating from the ER to CpG DNA in the lysosome.
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.
Latz
Eicke
E
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Lazare Research Building 308, 364 Plantation Street, Worcester, MA 01605, USA.
Schoenemeyer
Annett
A
Visintin
Alberto
A
Fitzgerald
Katherine A
KA
Monks
Brian G
BG
Knetter
Cathrine F
CF
Lien
Egil
E
Nilsen
Nadra J
NJ
Espevik
Terje
T
Golenbock
Douglas T
DT
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D001693:Biological Transport, Active; D002460:Cell Line; D018899:CpG Islands / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics / Q000276:immunology; D008247:Lysosomes / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors