Benedetto, Roberta and Ousingsawat, Jiraporn and Cabrita, Ines and Pinto, Madalena and Lerias, Joana R. and Wanitchakool, Podchanart and Schreiber, Rainer and Kunzelmann, Karl (2019) Plasma membrane-localized TMEM16 proteins are indispensable for expression of CFTR. JOURNAL OF MOLECULAR MEDICINE-JMM, 97 (5). pp. 711-722. ISSN 0946-2716, 1432-1440
Full text not available from this repository. (Request a copy)Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is the secretory chloride channel in epithelial tissues that has a central role in cystic fibrosis (CF) lung and gastrointestinal disease. A recent publication demonstrates a close association between CFTR and TMEM16A, the calcium-activated chloride channel. Thus, no CFTR chloride currents could be detected in airways and large intestine from mice lacking epithelial expression of TMEM16A. Here, we demonstrate that another plasma membrane-localized TMEM16 paralogue, TMEM16F, can compensate for the lack of TMEM16A. Using TMEM16 knockout mice, human lymphocytes, and a number of human cell lines with endogenous protein expression or heterologous expression, we demonstrate that CFTR can only function in the presence of either TMEM16A or TMEM16F. Double knockout of intestinal epithelial TMEM16A/F expression did not produce offsprings, suggesting a lethal phenotype in utero. Plasma membrane-localized TMEM16A or TMEM16F is required for exocytosis and expression of CFTR in the plasma membrane. TMEM16A/F proteins may therefore have an impact on disease severity in CF. Key messages Cystic fibrosis is caused by the defective Cl- channel cystic fibrosis transmembrane conductance regulator (CFTR). A close relationship exists between CFTR and the calcium-activated chloride channels TMEM16A/TMEM16F. In conditional airway and intestinal knockout mice, lymphocytes from Scott disease patients and in overexpressing cells, CFTR is not functional in the absence of TMEM16A and TMEM16F. TMEM16A and TMEM16F support membrane exocytosis and are essential for plasma membrane insertion of CFTR.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CALCIUM; ANOCTAMINS; ACTIVATION; SECRETION; SIGNALS; ANO1; CFTR; Cystic fibrosis transmembrane conductance regulator; Cystic fibrosis; CF; TMEM16A; Anoctamin 1; TMEM16F; Anoctamin 6; Ca2+-activated Cl- channel; Phospholipid scramblase |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Apr 2020 07:50 |
| Last Modified: | 09 Apr 2020 07:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27105 |
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