Document Detail


Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A-induced cytotoxicity.
MedLine Citation:
PMID:  17948127     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Wojciech Ornatowski; Jens F Poschet; Elizabeth Perkett; Jennifer L Taylor-Cousar; Vojo Deretic
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  117     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2007 Nov 
Date Detail:
Created Date:  2007-11-02     Completed Date:  2008-04-02     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3489-97     Citation Subset:  AIM; IM    
Affiliation:
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
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MeSH Terms
Descriptor/Qualifier:
ADP Ribose Transferases / 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:
AI 31139/AI/NIAID NIH HHS; AI 50825/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
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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