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Defective CFTR apical endocytosis and enterocyte brush border in myosin VI-deficient mice
1Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. nameen@pitt.edu
Abstract:
In polarized epithelial cells such as those that line the inner ear, kidney and gut, myosin VI has been localized to the intermicrovillar domains where it is proposed to regulate clathrin-dependent endocytosis; however, a direct role for myosin VI in apical endocytosis has not been shown. We examined the apical membrane distribution and endocytosis of cystic fibrosis transmembrane conductance regulator (CFTR) in myosin VI-deficient Snell's Waltzer Myo6((sv/sv)) mice. Confocal microscopy and cell-surface biotinylation confirmed that surface levels of CFTR in the intestine of Myo6((sv/sv)) mice were markedly higher, and CFTR internalization from the apical plasma membrane was reduced compared with heterozygous controls. Consistent with a defect in CFTR endocytosis and accumulation at the cell surface, exaggerated CFTR-mediated fluid secretion was observed in Myo6((sv/sv)) mice following treatment of isolated jejunum with the cyclic GMP-activated heat stable enterotoxin. These data establish that myosin VI modulates apical endocytosis and may be an important physiological modulator of CFTR function and CFTR-associated secretory diarrhea in the gut.
Insights
Myosin VI deficiency impairs apical endocytosis of cystic fibrosis transmembrane conductance regulator (CFTR) in the gut. This leads to increased CFTR on the cell surface and exaggerated fluid secretion, highlighting myosin VI's role in regulating CFTR function.
Area of Science:
- Cell Biology
- Molecular Biology
- Physiology
Background:
- Polarized epithelial cells utilize endocytosis for apical membrane regulation.
- Myosin VI is localized to intermicrovillar domains and implicated in clathrin-dependent endocytosis.
- A direct role for myosin VI in apical endocytosis remains unestablished.
Purpose of the Study:
- To investigate the role of myosin VI in the apical endocytosis of cystic fibrosis transmembrane conductance regulator (CFTR).
- To determine the impact of myosin VI deficiency on CFTR localization and function in the intestine.
Main Methods:
- Utilized Snell's Waltzer (Myo6((sv/sv))) mice, which are deficient in myosin VI.
- Employed confocal microscopy and cell-surface biotinylation to assess CFTR distribution and internalization.
- Examined CFTR-mediated fluid secretion in isolated jejunum following heat-stable enterotoxin treatment.
Main Results:
- Myosin VI-deficient mice exhibited significantly higher surface levels of CFTR in the intestine.
- CFTR internalization from the apical plasma membrane was reduced in myosin VI-deficient mice.
- Exaggerated CFTR-mediated fluid secretion was observed in Myo6((sv/sv)) mice.
Conclusions:
- Myosin VI directly modulates apical endocytosis in polarized epithelial cells.
- Myosin VI is a key regulator of CFTR function and may influence CFTR-associated secretory diarrhea.
- These findings establish a novel physiological role for myosin VI in intestinal epithelial transport.
