TLR9 regulation by proteolysis: a friend or a foe

Intracellular TLRs sense viral and bacterial nucleic acids from a wide variety of pathogens. Previous studies have shown that TLR9 requires processing for signalling. Following proteolysis, a fragment corresponding to the C-terminal part of TLR9 was shown to bind MyD88 and to induce signalling when cells were stimulated with TLR9 ligands. In this issue of the European Journal of Immunology, a study provides evidence that another proteolytic fragment of TLR9 is generated, different to that described previously, consisting of amino acids 1-723 which mediates inhibition of TLR9 signalling. These results suggest that proteolysis undoubtedly is a key step in TLR9 regulation.