| First Author | Wan T | Year | 2010 |
| Journal | J Biol Chem | Volume | 285 |
| Issue | 6 | Pages | 3750-7 |
| PubMed ID | 19948740 | Mgi Jnum | J:159941 |
| Mgi Id | MGI:4453088 | Doi | 10.1074/jbc.M109.069385 |
| Citation | Wan T, et al. (2010) AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling. J Biol Chem 285(6):3750-7 |
| abstractText | Toll-like receptor 4 (TLR4) is unique among the Toll-like receptors in its ability to utilize TLR/IL1R-domain-containing adaptor protein (TIRAP), which recruits TLR4-MyD88 to phosphatidylinositol 4,5-bisphosphate (PIP(2))-rich sites on the plasma membrane, to activate NF-kappaB and MAPK pathways. Here, we show that AIP1 disrupts formation of the TLR4- TIRAP-MyD88 complex without directly binding to any of the complex components. AIP1 via its pleckstrin homology and C2 domains binds to phosphatidylinositol 4-phosphate, a lipid precursor of PIP(2). Knock-out of AIP1 in cells increases and overexpression of AIP1 reduces cellular PIP(2) levels. We further show that AIP1 is a novel GTPase-activating protein (GAP) for Arf6, a small GTPase regulating cellular PIP(2) production and formation of the TLR4-TIRAP-MyD88 complex. Thus, deletion of the GAP domain on AIP1 results in a loss of its ability to mediate the inhibition of Arf6- and TLR4-induced signaling events. We conclude that AIP1 functions as a novel Arf6-GAP to negatively regulate PIP(2)-dependent TLR4-TIRAP-MyD88 signaling. |
