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

Research output: Contribution to journalArticle

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 ATRL-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 ΔF508-CFTR. Silencing STX6 has no effect on ΔF508-CFTR expression. However, overexpression of STX6 coimmunoprecipitates with and reduces temperature-rescued Δ508-CFTR that escapes ER degradation. Conversely, silencing STX6 enhances the effect of low temperature in rescuing ΔF508-CFTR. Finally, in human bronchial epithelial cells, silencing endogenous STX6 leads to increases in protein levels and Cl- currents of both wild-type and temperaturerescued CFTR. We have identified STX6 as a new component of the CAL complex that regulates the abundance and function of CFTR at the post-ER level. Our results suggest a therapeutic role of STX6 in enhancing rescued ΔF508-CFTR.

Original languageEnglish (US)
Pages (from-to)1178-1187
Number of pages10
JournalMolecular Biology of the Cell
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2010

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Qa-SNARE Proteins
Cystic Fibrosis Transmembrane Conductance Regulator
PDZ Domains
SNARE Proteins
Temperature

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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Syntaxin 6 and CAL mediate the degradation of the cystic fibrosis transmembrane conductance regulator. / Cheng, Jie; Cebotaru, Valeriu; Cebotaru, Liudmila; Guggino, William B.

In: Molecular Biology of the Cell, Vol. 21, No. 7, 01.04.2010, p. 1178-1187.

Research output: Contribution to journalArticle

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