Role of MyD88 in Phosphatidylinositol 3-Kinase Activation by Flagellin/Toll-like Receptor 5 Engagement in Colonic

Bacterial flagellin, recognized by Toll-like receptor (TLR) 5, issuggested to be involved in colonic inflammation. However, thedetailedsignalingmechanismsmediatedbyflagellin/TLR5engage-ment are not clear. Here we dissected the biochemical mechanismby which TLR5 engagement mediates phosphatidylinositol 3-ki-nase (PI3K) activation in colonic epithelial cells. We demonstratethat silencing TLR5 expression in nontransformed human colonicepithelial cells blocks flagellin-induced PI3K activation, indicatingspecific activation of PI3K by flagellin/TLR5 engagement. More-over,wedeterminethatTLR5recruitsthep85regulatorysubunitofPI3K to its cytoplasmic TIR domain in response to flagellin. How-ever, the Src homology binding “Y