Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner.
Eur J Immunol
; 34(9): 2541-50, 2004 Sep.
Article
em En
| MEDLINE
| ID: mdl-15307186
ABSTRACT
Toll-like receptors (TLR) recognize bacterial and viral components, but direct interaction of receptor and ligand is unclear. Here, we demonstrate that TLR9 binds directly and sequence-specifically to single-stranded unmethylated CpG-DNA containing a phosphodiester backbone. TLR9-CpG-DNA interaction occurs at the acidic pH (6.5-5.0) found in endosomes and lysosomes. By sequence comparison we identified a potential CpG-DNA binding domain homologous to that described for methyl-CpG-DNA binding proteins. Amino acid substitutions in this region abrogated CpG-DNA binding and led to loss of NF-kappaB activation. Furthermore, chloroquine and quinacrine, therapeutic agents for autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, directly blocked TLR9-CpG-DNA interaction but not TLR2-Pam3Cys binding. Our results demonstrate direct binding of TLR9 to CpG-DNA and suggest that the therapeutic activity of chloroquine and quinacrine in autoimmune diseases may be due to its activity as a TLR9 antagonist and inhibitor of endosomal acidification.
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Base de dados:
MEDLINE
Assunto principal:
DNA de Cadeia Simples
/
Glicoproteínas de Membrana
/
Receptores de Superfície Celular
/
Ilhas de CpG
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article