Abstract：
:Efficient trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) to and from the cell surface is essential for maintaining channel density at the plasma membrane (PM) and ensuring proper physiological activity. The most common mutation, F508del, exhibits reduced surface expression and impaired function despite treatment with currently available pharmacological small molecules, called correctors. To gain more detailed insight into whether CFTR enters compartments that allow corrector stabilization in the cell periphery, we investigated the peripheral trafficking itineraries and kinetics of wild type (WT) and F508del in living cells using high-speed fluorescence microscopy together with fluorogen activating protein detection. We directly visualized internalization and accumulation of CFTR WT from the PM to a perinuclear compartment that colocalized with the endosomal recycling compartment (ERC) markers Rab11 and EHD1, reaching steady-state distribution by 25 minutes. Stimulation by protein kinase A (PKA) depleted this intracellular pool and redistributed CFTR channels to the cell surface, elicited by reduced endocytosis and active translocation to the PM. Corrector or temperature rescue of F508del also resulted in targeting to the ERC and exhibited subsequent PKA-stimulated trafficking to the PM. Corrector treatment (24 hours) led to persistent residence of F508del in the ERC, while thermally destabilized F508del was targeted to lysosomal compartments by 3 hours. Acute addition of individual correctors, C4 or C18, acted on peripheral trafficking steps to partially block lysosomal targeting of thermally destabilized F508del. Taken together, corrector treatment redirects F508del trafficking from a degradative pathway to a regulated recycling route, and proteins that mediate this process become potential targets for improving the efficacy of current and future correctors.
journal_name
J Cell Scijournal_title
Journal of cell scienceauthors
Holleran JP,Zeng J,Frizzell RA,Watkins SCdoi
10.1242/jcs.120196subject
Has Abstractpub_date
2013-06-15 00:00:00pages
2692-703issue
Pt 12eissn
0021-9533issn
1477-9137pii
jcs.120196journal_volume
126pub_type
杂志文章abstract：:Stages of meiosis from the bluebell Endymion non-scriptus (L.) were studied by electron microscopy. The nucleolus went through the process of segregation at the beginning of meiosis with the movement to its surface of a pale-staining region. This region was shown to be the same as that called the 'L zone' or lacunae o...
journal_title：Journal of cell science
pub_type： 杂志文章
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更新日期：1976-10-01 00:00:00
abstract：:Mechanical cues are essential for the regulation of cell and tissue physiology. Hence, it has become an utmost necessity for cell biologists to account for those mechanical parameters when investigating biological processes and they need devices to manipulate cells accordingly. Here, we report a simple mechanical cell...
journal_title：Journal of cell science
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abstract：:Sperm fertilization reactions of Limulus polyphemus were examined by scanning electron and/or light microscopy. The following were considered: sperm motility, attachment of sperm to egg, acrosome reaction, and penetration of the acrosomal filament. The spermatozoa after semination are non-motile and become active only...
journal_title：Journal of cell science
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更新日期：1976-12-01 00:00:00
abstract：:Mutations within connexin50 (Cx50) have been linked to various cataract phenotypes. To determine the mechanism behind cataract formation we used the paired Xenopus oocyte system in conjunction with transfected HeLa cells and genetically engineered mouse models to examine the functional characteristics of gap junctions...
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journal_title：Journal of cell science
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更新日期：2010-12-15 00:00:00
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更新日期：2013-03-15 00:00:00
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journal_title：Journal of cell science
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更新日期：1995-06-01 00:00:00
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更新日期：2019-05-15 00:00:00
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journal_title：Journal of cell science
pub_type： 杂志文章
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更新日期：2011-07-01 00:00:00
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journal_title：Journal of cell science
pub_type： 杂志文章,评审
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更新日期：2016-10-15 00:00:00
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journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.209924
更新日期：2018-02-22 00:00:00
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journal_title：Journal of cell science
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doi：10.1242/jcs.038356
更新日期：2009-02-15 00:00:00
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journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.114231
更新日期：2013-01-15 00:00:00
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journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1992-02-01 00:00:00
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journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1999-05-01 00:00:00
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journal_title：Journal of cell science
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doi：
更新日期：1984-10-01 00:00:00
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journal_title：Journal of cell science
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doi：
更新日期：1993-11-01 00:00:00
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journal_title：Journal of cell science
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journal_title：Journal of cell science
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doi：
更新日期：1996-05-01 00:00:00
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journal_title：Journal of cell science
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更新日期：2002-07-15 00:00:00
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更新日期：1978-06-01 00:00:00
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