TLR9 signaling requires ligand-induced phosphorylation of two specific tyrosine residues by EGFR and Syk

Toll-like receptors (TLRs) are critical components of cellular innate immune responses to microbial infection or tissue damage. TLRs are transmembrane proteins that require activation to mount a successful host response; TLR mutations are associated with human diseases. TLR ligands are also used as vaccine adjuvants to amplify the inflammatory responses of the host, activation of TLRs, and their regulation are essential. Here, we report the molecular mechanisms of TLR9 activation by tyrosine phosphorylation of its cytoplasmic domain. TLR9 interacts with EGFR and Syk, the tyrosine kinases, which phosphorylate two specific tyrosine residues on the TLR9 cytoplasmic domain. Mutation of these tyrosine residues or deficiency of these tyrosine kinases leads to impaired TLR9 signaling. Therefore, our results elucidate the early events of TLR9 signaling with implications in inflammatory diseases.