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      Defects in Processing and Trafficking of Cystic Fibrosis Transmembrane Conductance Regulator

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          Abstract

          In most epithelial tissues Cl<sup>–</sup> transport relies on the cystic fibrosis transmembrane conductance regulator (CFTR) which has dual function as a Cl<sup>–</sup> channel and as a regulator of other ion channels. More than 900 different mutations in the CFTR gene are the cause for defective transport of Cl<sup>–</sup> and Na<sup>+</sup> and impaired secretion or absorption of electrolytes in cystic fibrosis. However, the CFTR mutation ΔF508 is the most common reason for the frequently inherited disease among the Caucasian population. Maturation and processing of ΔF508-CFTR is defective which leads to expression of only very little but functional CFTR in the cell membrane. Understanding the processing and trafficking of CFTR may give a clue to the question as to how the expression and residual function of ΔF508-CFTR can be enhanced, and may lead to the development of new pharmacological tools for the treatment of cystic fibrosis.

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          Most cited references 37

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          Aggresomes: A Cellular Response to Misfolded Proteins

          Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein and how they are delivered to cytoplasmic inclusions are not known. We have investigated the intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR), an inefficiently folded integral membrane protein which is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells led to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy with immunogold labeling, we demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which we have termed the aggresome. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevented the degradation of unassembled presenilin-1 molecules leading to their aggregation and deposition in aggresomes. These data lead us to propose that aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.
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            Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin.

            The cellular activity of several regulatory and signal transduction proteins, which depend on the Hsp90 molecular chaperone for folding, is markedly decreased by geldanamycin and by radicicol (monorden). We now show that these unrelated compounds both bind to the N-terminal ATP/ADP-binding domain of Hsp90, with radicicol displaying nanomolar affinity, and both inhibit the inherent ATPase activity of Hsp90 which is essential for its function in vivo. Crystal structure determinations of Hsp90 N-terminal domain complexes with geldanamycin and radicicol identify key aspects of their nucleotide mimicry and suggest a rational basis for the design of novel antichaperone drugs.
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              Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid.

              Despite an increased understanding of the cellular and molecular biology of the CFTR Cl- channel, it is not known how defective Cl- transport across airway epithelia causes chronic bacterial infections in cystic fibrosis (CF) airways. Here, we show that common CF pathogens were killed when added to the apical surface of normal airway epithelia. In contrast, these bacteria multiplied on CF epithelia. We found that bactericidal activity was present in airway surface fluid of both normal and CF epithelia. However, because bacterial killing required a low NaCl concentration and because CF surface fluid has a high NaCl concentration, CF epithelia failed to kill bacteria. This defect was corrected by reducing the NaCl concentration on CF epithelia. These data explain how the loss of CFTR Cl- channels may lead to lung disease and suggest new approaches to therapy.
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                Author and article information

                Journal
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                978-3-8055-7143-2
                978-3-318-00633-9
                1660-2129
                2000
                December 2000
                15 September 2000
                : 8
                : 6
                : 332-342
                Affiliations
                aDepartment of Physiology and Pharmacology, University of Queensland, St. Lucia, Brisbane, Australia, and bPhysiologisches Institut, Albert-Ludwigs-Universität Freiburg, Deutschland
                Article
                20687 Exp Nephrol 2000;8:332–342
                10.1159/000020687
                11014930
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, References: 158, Pages: 11
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/20687
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