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

M Rutz, J Metzger, T Gellert, P Luppa… - European journal of …, 2004 - Wiley Online Library
M Rutz, J Metzger, T Gellert, P Luppa, GB Lipford, H Wagner, S Bauer
European journal of immunology, 2004Wiley Online Library
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 …
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‐κB 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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