Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A-induced cytotoxicity.
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.
Ornatowski
Wojciech
W
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
Poschet
Jens F
JF
Perkett
Elizabeth
E
Taylor-Cousar
Jennifer L
JL
Deretic
Vojo
V
D036002:ADP Ribose Transferases / Q000633:toxicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D005098:Exotoxins / Q000633:toxicity*; D025461:Feedback, Physiological; D045683:Furin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D037521:Virulence Factors / Q000633:toxicity*; D021601:trans-Golgi Network / Q000201:enzymology; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005098:Exotoxins; D045683:Furin; D052247:Nitric Oxide Synthase Type II; D016212:Transforming Growth Factor beta; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C468731:FURIN protein, human