Dataset Information

AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling.

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.

SUBMITTER: Wan T

PROVIDER: S-EPMC2823516 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling.

Wan Ting T Liu Ting T Zhang Haifeng H Tang Shibo S Min Wang W

The Journal of biological chemistry 20091130 6

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 phosphatid ...[more]

PMID: 19948740

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Project description:BackgroundOrgans are programmed to acquire a particular size during development, but the regulatory mechanisms that dictate when dividing progenitor cells should permanently exit the cell cycle and stop producing additional daughter cells are poorly understood. In differentiated tissues, tumor suppressor genes maintain a constant cell number and intact tissue architecture by controlling proliferation, apoptosis and cell dispersal. Here we report a similar role for two tumor suppressor genes, the Zac1 zinc finger transcription factor and that encoding the cytokine TGFbetaII, in the developing retina.ResultsUsing loss and gain-of-function approaches, we show that Zac1 is an essential negative regulator of retinal size. Zac1 mutants develop hypercellular retinae due to increased progenitor cell proliferation and reduced apoptosis at late developmental stages. Consequently, supernumerary rod photoreceptors and amacrine cells are generated, the latter of which form an ectopic cellular layer, while other retinal cells are present in their normal number and location. Strikingly, Zac1 functions as a direct negative regulator of a rod fate, while acting cell non-autonomously to modulate amacrine cell number. We implicate TGFbetaII, another tumor suppressor and cytokine, as a Zac1-dependent amacrine cell negative feedback signal. TGFbetaII and phospho-Smad2/3, its downstream effector, are expressed at reduced levels in Zac1 mutant retinae, and exogenous TGFbetaII relieves the mutant amacrine cell phenotype. Moreover, treatment of wild-type retinae with a soluble TGFbeta inhibitor and TGFbeta receptor II (TGFbetaRII) conditional mutants generate excess amacrine cells, phenocopying the Zac1 mutant phenotype.ConclusionWe show here that Zac1 has an essential role in cell number control during retinal development, akin to its role in tumor surveillance in mature tissues. Furthermore, we demonstrate that Zac1 employs a novel cell non-autonomous strategy to regulate amacrine cell number, acting in cooperation with a second tumor suppressor gene, TGFbetaII, through a negative feedback pathway. This raises the intriguing possibility that tumorigenicity may also be associated with the loss of feedback inhibition in mature tissues.

Dataset Information

AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling.

Publications

AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling.

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