Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner.

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. Copyright 2004 Wiley-VCH Verlag GmbH & Co.

Citation

Mark Rutz, Jochen Metzger, Tanja Gellert, Peter Luppa, Grayson B Lipford, Hermann Wagner, Stefan Bauer. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. European journal of immunology. 2004 Sep;34(9):2541-50

Mesh Tags

Substances

PMID: 15307186

search → result