Caveolin-1 Tyr14 phosphorylation induces interaction with TLR4 in endothelial cells and mediates MyD88-dependent signaling and sepsis-induced lung inflammation.

Abstract	Activation of TLR4 by the endotoxin LPS is a critical event in the pathogenesis of Gram-negative sepsis. Caveolin-1, the signaling protein associated with caveolae, is implicated in regulating the lung inflammatory response to LPS; however, the mechanism is not understood. In this study, we investigated the role of caveolin-1 in regulating TLR4 signaling in endothelial cells. We observed that LPS interaction with CD14 in endothelial cells induced Src-dependent caveolin-1 phosphorylation at Tyr(14). Using a TLR4-MD2-CD14-transfected HEK-293 cell line and caveolin-1-deficient (cav-1(-/-)) mouse lung microvascular endothelial cells, we demonstrated that caveolin-1 phosphorylation at Tyr(14) following LPS exposure induced caveolin-1 and TLR4 interaction and, thereby, TLR4 activation of MyD88, leading to NF-κB activation and generation of proinflammatory cytokines. Exogenous expression of phosphorylation-deficient Y14F caveolin-1 mutant in cav-1(-/-) mouse pulmonary vasculature rendered the mice resistant to LPS compared with reintroduction of wild-type caveolin-1. Thus, caveolin-1 Y14 phosphorylation was required for the interaction with TLR4 and activation of TLR4-MyD88 signaling and sepsis-induced lung inflammation. Inhibiting caveolin-1 Tyr(14) phosphorylation and resultant inactivation of TLR4 signaling in pulmonary vascular endothelial cells represent a novel strategy for preventing sepsis-induced lung inflammation and injury.
Authors	Hao Jiao, Yang Zhang, Zhibo Yan, Zhen-Guo Wang, Gongjian Liu, Richard D Minshall, Asrar B Malik, Guochang Hu
Journal	Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 191 Issue 12 Pg. 6191-9 (Dec 15 2013) ISSN: 1550-6606 [Electronic] United States
PMID	24244013 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Caveolin 1 I-kappa B Proteins Interleukin-6 Lipopolysaccharides Myd88 protein, mouse Myeloid Differentiation Factor 88 NFKBIA protein, human Nfkbia protein, mouse Recombinant Fusion Proteins TLR4 protein, human Tlr4 protein, mouse Toll-Like Receptor 4 Tumor Necrosis Factor-alpha NF-KappaB Inhibitor alpha Phosphotyrosine src-Family Kinases Interleukin-1 Receptor-Associated Kinases Irak1 protein, mouse
Topics	Amino Acid Substitution Animals Caveolin 1 (chemistry, genetics, metabolism) Cells, Cultured Endothelial Cells (metabolism) Endothelium, Vascular (cytology) Endotoxemia (pathology) Humans I-kappa B Proteins (metabolism) Inflammation Interleukin-1 Receptor-Associated Kinases (metabolism) Interleukin-6 (biosynthesis, genetics) Lipopolysaccharides (toxicity) Lung (blood supply, pathology) Mice Microvessels (cytology) Mutation, Missense Myeloid Differentiation Factor 88 (physiology) NF-KappaB Inhibitor alpha Phosphorylation Phosphotyrosine (biosynthesis, physiology) Point Mutation Protein Processing, Post-Translational Recombinant Fusion Proteins (metabolism) Toll-Like Receptor 4 (physiology) Transfection Tumor Necrosis Factor-alpha (genetics) src-Family Kinases (metabolism)

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