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CFTR in a lipid raft-TNFR1 complex modulates gap junctional intercellular communication and IL-8 secretion

Borot, Florence
Ollero, Mario
Stanton, Bruce A.
Published in Biochimica et biophysica acta. 2008, vol. 1783, no. 5, p. 779-88
Abstract Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause a chronic inflammatory response in the lung of patients with Cystic Fibrosis (CF). We have showed that TNF-alpha signaling through the Src family tyrosine kinases (SFKs) was defective as determined by an inability of TNF-alpha to regulate gap junctional communication (GJIC) in CF cells. Here, we sought to elucidate the mechanisms linking TNF-alpha signaling to the functions of CFTR at the molecular level. In a MDCKI epithelial cell model expressing wild-type (WtCFTR) or mutant CFTR lacking its PDZ-interacting motif (CFTR-DeltaTRL), TNF-alpha increased the amount of WtCFTR but not CFTR-DeltaTRL in detergent-resistant membrane microdomains (DRMs). This recruitment was modulated by SFK activity and associated with DRM localization of TNFR1 and c-Src. Activation of TNFR1 signaling also decreased GJIC and markedly stimulated IL-8 production in WtCFTR cells. In contrast, the absence of CFTR in DRMs was associated with abnormal TNFR1 signaling as revealed by no recruitment of TNFR1 and c-Src to lipid rafts in CFTR-DeltaTRL cells and loss of regulation of GJIC and IL-8 secretion. These results suggest that localization of CFTR in lipid rafts in association with c-Src and TNFR1 provides a responsive signaling complex to regulate GJIC and cytokine signaling.
Keywords Cell CommunicationCell LineConnexin 43Cystic Fibrosis Transmembrane Conductance RegulatorDogsGap JunctionsInterleukin-8Membrane MicrodomainsMembrane ProteinsProto-Oncogene Proteins pp60(c-src)ReceptorsTumor Necrosis FactorType ISequence DeletionSignal TransductionTumor Necrosis Factor-alphaSrc-Family Kinases
PMID: 18255040
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Research groups L'athérosclérose (665)
Mucoviscidose et jonctions GAP (229)
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DUDEZ, Tecla et al. CFTR in a lipid raft-TNFR1 complex modulates gap junctional intercellular communication and IL-8 secretion. In: Biochimica et biophysica acta, 2008, vol. 1783, n° 5, p. 779-88. doi: 10.1016/j.bbamcr.2008.01.007 https://archive-ouverte.unige.ch/unige:862

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Deposited on : 2009-02-19

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