2. Academic Validation
  3. AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling

AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling

  • J Biol Chem. 2010 Feb 5;285(6):3750-3757. doi: 10.1074/jbc.M109.069385.
Ting Wan 1,  Ting Liu 2,  Haifeng Zhang 2,  Shibo Tang 3,  Wang Min 4
Affiliations

Affiliations

  • 1 From the Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520 and; the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China.
  • 2 From the Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520 and.
  • 3 the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China. Electronic address: tangsb@mail.sysu.edu.cn.
  • 4 From the Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520 and; the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China. Electronic address: wang.min@yale.edu.
PMID: 19948740 DOI: 10.1074/jbc.M109.069385
Abstract

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.

Figures