An alanine to proline mutation in the BB-loop of Toll-like receptor 3 TIR domain switches signalling adaptor specificity from TRIF to MyD88

摘要

A functionally important proline residue is highly conserved in the cytosolic TIR signalling domains of human Toll-like receptors (TLRs). The anti-viral Toll, TLR3, is unusual as it has alanine instead of proline at this position and is the only human TLR that associates directly with the adaptor molecule TRIF rather than MyD88. Here we report that a mutant TLR3 that substitutes the BB-loop alanine for proline (A795P) enhances NF-κB activation but is incapable of mediating TRIF dependent IRF3 responses. Wild-type and A795P TLR3 associate constitutively with both TRIF and MyD88 and activation induces additional binding of TRIF to the wild-type and of MyD88 to the A795P mutant receptors respectively. In addition activation of A795P but not wild-type TLR3 leads to the recruitment TRAF6, a downstream signal transducer of the MyD88 dependent pathway. These results show that adaptor specificity can be conferred by minimal determinants of the TIR domain.