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      Regulation of Transporters and Channels by Membrane-Trafficking Complexes in Epithelial Cells

      review-article
      Cold Spring Harbor Perspectives in Biology
      Cold Spring Harbor Laboratory Press

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          Abstract

          Epithelial cells transport substances through protein channels that are localized to the apical or basolateral membranes. Progress is being made to characterize the machinery that establishes and maintains this polarity.

          Abstract

          The vectorial secretion and absorption of fluid and solutes by epithelial cells is dependent on the polarized expression of membrane solute transporters and channels at the apical and basolateral membranes. The establishment and maintenance of this polarized expression of transporters and channels are affected by divers protein-trafficking complexes. Moreover, regulation of the magnitude of transport is often under control of physiological stimuli, again through the interaction of transporters and channels with protein-trafficking complexes. This review highlights the value in utilizing transporters and channels as cargo to characterize core trafficking machinery by which epithelial cells establish and maintain their polarized expression, and how this machinery regulates fluid and solute transport in response to physiological stimuli.

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          Most cited references181

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          Retromer.

          The retromer is a heteropentameric complex that associates with the cytosolic face of endosomes and mediates retrograde transport of transmembrane cargo from endosomes to the trans-Golgi network. The mammalian retromer complex comprises a sorting nexin dimer composed of a still undefined combination of SNX1, SNX2, SNX5 and SNX6, and a cargo-recognition trimer composed of Vps26, Vps29 and Vps35. The SNX subunits contain PX and BAR domains that allow binding to PI(3)P enriched, highly curved membranes of endosomal vesicles and tubules, while Vps26, Vps29 and Vps35 have arrestin, phosphoesterase and alpha-solenoid folds, respectively. Recent studies have implicated retromer in a broad range of physiological, developmental and pathological processes, underscoring the critical nature of retrograde transport mediated by this complex.
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            Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway.

            The most prevalent disease-causing mutation of CFTR is the deletion of Phe508 (ΔF508), which leads to defects in conventional Golgi-mediated exocytosis and cell surface expression. We report that ΔF508-CFTR surface expression can be rescued in vitro and in vivo by directing it to an unconventional GRASP-dependent secretion pathway. An integrated molecular and physiological analysis indicates that mechanisms associated with ER stress induce cell surface trafficking of the ER core-glycosylated wild-type and ΔF508-CFTR via the GRASP-dependent pathway. Phosphorylation of a specific site of GRASP and the PDZ-based interaction between GRASP and CFTR are critical for this unconventional surface trafficking. Remarkably, transgenic expression of GRASP in ΔF508-CFTR mice restores CFTR function and rescues mouse survival without apparent toxicity. These findings provide insight into how unconventional protein secretion is activated, and offer a potential therapeutic strategy for the treatment of cystic fibrosis and perhaps diseases stemming from other misfolded proteins. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: structures, functions and roles in disease.

              The mammalian genome encodes 49 proteins that possess a PX (phox-homology) domain, responsible for membrane attachment to organelles of the secretory and endocytic system via binding of phosphoinositide lipids. The PX domain proteins, most of which are classified as SNXs (sorting nexins), constitute an extremely diverse family of molecules that play varied roles in membrane trafficking, cell signalling, membrane remodelling and organelle motility. In the present review, we present an overview of the family, incorporating recent functional and structural insights, and propose an updated classification of the proteins into distinct subfamilies on the basis of these insights. Almost all PX domain proteins bind PtdIns3P and are recruited to early endosomal membranes. Although other specificities and localizations have been reported for a select few family members, the molecular basis for binding to other lipids is still not clear. The PX domain is also emerging as an important protein-protein interaction domain, binding endocytic and exocytic machinery, transmembrane proteins and many other molecules. A comprehensive survey of the molecular interactions governed by PX proteins highlights the functional diversity of the family as trafficking cargo adaptors and membrane-associated scaffolds regulating cell signalling. Finally, we examine the mounting evidence linking PX proteins to different disorders, in particular focusing on their emerging importance in both pathogen invasion and amyloid production in Alzheimer's disease.
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                Author and article information

                Journal
                Cold Spring Harb Perspect Biol
                Cold Spring Harb Perspect Biol
                cshperspect
                cshperspect
                Cold Spring Harbor Perspectives in Biology
                Cold Spring Harbor Laboratory Press (Cold Spring Harbor, New York )
                1943-0264
                November 2017
                : 9
                : 11
                : a027839
                Affiliations
                Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089-9121
                Author notes
                Correspondence: cokamoto@ 123456usc.edu

                Editor: Keith E. Mostov

                Additional Perspectives on Cell Polarity available at www.cshperspectives.org

                Article
                PMC5666629 PMC5666629 5666629 a027839
                10.1101/cshperspect.a027839
                5666629
                28246186
                eb4ec1a7-6f75-4776-9fa4-d427750cc591
                Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved
                History
                Page count
                Pages: 20
                Categories
                119
                PERSPECTIVES
                Cell Biology

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