Syntaxin 6 and CAL mediate the degradation of the cystic fibrosis transmembrane conductance regulator.

Molecular Biology of the Cell
Jie ChengWilliam B Guggino

Abstract

The PDZ domain-containing protein CAL mediates lysosomal trafficking and degradation of CFTR. Here we demonstrate the involvement of a CAL-binding SNARE protein syntaxin 6 (STX6) in this process. Overexpression of STX6, which colocalizes and coimmunoprecipitates with CAL, dramatically reduces the steady-state level and stability of CFTR. Conversely, overexpression of a STX6 dominant-negative mutant increases CFTR. Silencing endogenous STX6 increases CFTR but has no effect on DeltaTRL-CFTR, which cannot bind to CAL. Silencing CAL eliminates the effect of STX6 on CFTR. Both results suggest a dependence of CAL on STX6 function. Consistent with its Golgi localization, STX6 does not bind to ER-localized DeltaF508-CFTR. Silencing STX6 has no effect on DeltaF508-CFTR expression. However, overexpression of STX6 coimmunoprecipitates with and reduces temperature-rescued DeltaF508-CFTR that escapes ER degradation. Conversely, silencing STX6 enhances the effect of low temperature in rescuing DeltaF508-CFTR. Finally, in human bronchial epithelial cells, silencing endogenous STX6 leads to increases in protein levels and Cl(-) currents of both wild-type and temperature-rescued CFTR. We have identified STX6 as a new component of the CAL comple...Continue Reading

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Citations

Jun 8, 2012·Cold Spring Harbor Perspectives in Medicine·Raymond A Frizzell, John W Hanrahan
Dec 6, 2012·BMC Medical Genomics·Philip BeinekeUNKNOWN PREDICT Investigators
Aug 4, 2012·Journal of the American Society of Nephrology : JASN·Ying ChenHua A Jenny Lu
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Aug 13, 2021·Molecular Neurobiology·Malte KlüssendorfHans-Jürgen Kreienkamp

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Methods Mentioned

BETA
PCR
transfection
protein assay
immunoprecipitation
transfecting
confocal microscopy
immunodepletion
GTPase

Software Mentioned

Windows XP
Image Gauge
AllStars
Acquire and Analyze

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