| Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A-induced cytotoxicity. | |
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MedLine Citation:
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PMID: 17948127 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Progressive pulmonary disease and infections with Pseudomonas aeruginosa remain an intractable problem in cystic fibrosis (CF). At the cellular level, CF is characterized by organellar hyperacidification, which results in altered protein and lipid glycosylation. Altered pH of the trans-Golgi network (TGN) may further disrupt the protein processing and packaging that occurs in this organelle. Here we measured activity of the major TGN endoprotease furin and demonstrated a marked upregulation in human CF cells. Increased furin activity was linked to elevated production in CF of the immunosuppressive and tissue remodeling cytokine TGF-beta and its downstream effects, including macrophage deactivation and augmented collagen secretion by epithelial cells. As furin is responsible for the proteolytic processing of a range of endogenous and exogenous substrates including growth factors and bacterial toxins, we determined that elevated furin-dependent activation of exotoxin A caused increased cell death in CF respiratory epithelial cells compared with genetically matched CF transmembrane conductance regulator-corrected cells. Thus elevated furin levels in CF respiratory epithelial cells contributes to bacterial toxin-induced cell death, fibrosis, and local immunosuppression. These data suggest that the use of furin inhibitors may represent a strategy for pharmacotherapy in CF. |
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Authors:
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Wojciech Ornatowski; Jens F Poschet; Elizabeth Perkett; Jennifer L Taylor-Cousar; Vojo Deretic |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 117 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 2007 Nov |
Date Detail:
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Created Date: 2007-11-02 Completed Date: 2008-04-02 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 3489-97 Citation Subset: AIM; IM |
Affiliation:
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Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ADP Ribose Transferases
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toxicity* Bacterial Toxins / toxicity* Cell Line Cystic Fibrosis / metabolism* Cystic Fibrosis Transmembrane Conductance Regulator / genetics, metabolism Exotoxins / toxicity* Feedback, Physiological Furin / antagonists & inhibitors, genetics, metabolism* Humans Macrophages / metabolism Nitric Oxide Synthase Type II / metabolism Respiratory Mucosa / cytology, metabolism* Transforming Growth Factor beta / metabolism Virulence Factors / toxicity* trans-Golgi Network / enzymology |
| Grant Support | |
ID/Acronym/Agency:
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AI 31139/AI/NIAID NIH HHS; AI 50825/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bacterial Toxins; 0/Exotoxins; 0/Transforming Growth Factor beta; 0/Virulence Factors; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 2.4.2.-/ADP Ribose Transferases; EC 2.4.2.31/toxA protein, Pseudomonas aeruginosa; EC 3.4.21.75/FURIN protein, human; EC 3.4.21.75/Furin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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