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Research ArticleCell biology Free access | 10.1172/JCI31499

Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Wojciech Ornatowski,1 Jens F. Poschet,1 Elizabeth Perkett,2,3 Jennifer L. Taylor-Cousar,3,4 and Vojo Deretic1,2

1Department of Molecular Genetics and Microbiology, 2Department of Cell Biology and Physiology, 3Department of Pediatrics, and 4Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.

Address correspondence to: Vojo Deretic, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, MSC08-4660, 915 Camino de Salud, Albuquerque, New Mexico 87131, USA. Phone: (505) 272-0291; Fax: (505) 272-5309; E-mail: vderetic@salud.unm.edu.

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1Department of Molecular Genetics and Microbiology, 2Department of Cell Biology and Physiology, 3Department of Pediatrics, and 4Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.

Address correspondence to: Vojo Deretic, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, MSC08-4660, 915 Camino de Salud, Albuquerque, New Mexico 87131, USA. Phone: (505) 272-0291; Fax: (505) 272-5309; E-mail: vderetic@salud.unm.edu.

Find articles by Poschet, J. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, 2Department of Cell Biology and Physiology, 3Department of Pediatrics, and 4Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.

Address correspondence to: Vojo Deretic, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, MSC08-4660, 915 Camino de Salud, Albuquerque, New Mexico 87131, USA. Phone: (505) 272-0291; Fax: (505) 272-5309; E-mail: vderetic@salud.unm.edu.

Find articles by Perkett, E. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, 2Department of Cell Biology and Physiology, 3Department of Pediatrics, and 4Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.

Address correspondence to: Vojo Deretic, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, MSC08-4660, 915 Camino de Salud, Albuquerque, New Mexico 87131, USA. Phone: (505) 272-0291; Fax: (505) 272-5309; E-mail: vderetic@salud.unm.edu.

Find articles by Taylor-Cousar, J. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, 2Department of Cell Biology and Physiology, 3Department of Pediatrics, and 4Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.

Address correspondence to: Vojo Deretic, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, MSC08-4660, 915 Camino de Salud, Albuquerque, New Mexico 87131, USA. Phone: (505) 272-0291; Fax: (505) 272-5309; E-mail: vderetic@salud.unm.edu.

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Published October 18, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI31499.
© 2007 The American Society for Clinical Investigation
Published October 18, 2007 - Version history
Received: January 12, 2007; Accepted: August 14, 2007
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Abstract

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-β 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.

Version history
  • Version 1 (October 18, 2007): No description
  • Version 2 (November 1, 2007): No description
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