期刊
JOURNAL OF CELL SCIENCE
卷 132, 期 10, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.226886
关键词
CFTR; Airway epithelium; Polarity; Trafficking
类别
资金
- Canadian Institutes of Health Research [MOP-142221]
- National Institute of Diabetes and Digestive and Kidney Diseases [5R01DK075302]
- Cystic Fibrosis Canada
- Richard & Edith Strauss Fellowship, McGill Univeristy
Apical polarity of cystic fibrosis transmembrane conductance regulator (CFTR) is essential for solute and water transport in secretory epithelia and can be impaired in human diseases. Maintenance of apical polarity in the face of CFTR non-polarized delivery and inefficient apical retention of mutant CFTRs lacking PDZ-domain protein (NHERF1, also known as SLC9A3R1) interaction, remains enigmatic. Here, we show that basolateral CFTR delivery originates from biosynthetic (similar to 35%) and endocytic (similar to 65%) recycling missorting. Basolateral channels are retrieved via basolateral-to-apical transcytosis (hereafter denoted apical transcytosis), enhancing CFTR apical expression by two-fold and suppressing its degradation. In airway epithelia, CFTR transcytosis is microtubule-dependent but independent of Myo5B, Rab11 proteins and NHERF1 binding to its C-terminal DTRL motif. Increased basolateral delivery due to compromised apical recycling and accelerated internalization upon impaired NHERF1-CFTR association is largely counterbalanced by efficient CFTR basolateral internalization and apical transcytosis. Thus, transcytosis represents a previously unrecognized, but indispensable, mechanism for maintaining CFTR apical polarity that acts by attenuating its constitutive and mutation-induced basolateral missorting.
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