Proteases, cystic fibrosis and the epithelial sodium channel (ENaC)

Abstract

Proteases perform a diverse array of biological functions. From simple peptide digestion for nutrient absorption to complex signaling cascades, proteases are found in organisms from prokaryotes to humans. In the human airway, proteases are associated with the regulation of the airway surface liquid layer, tissue remodeling, host defense and pathogenic infection and inflammation. A number of proteases are released in the airways under both physiological and pathophysiological states by both the host and invading pathogens. In airway diseases such as cystic fibrosis, proteases have been shown to be associated with increased morbidity and airway disease progression. In this review, we focus on the regulation of proteases and discuss specifically those proteases found in human airways. Attention then shifts to the epithelial sodium channel (ENaC), which is regulated by proteolytic cleavage and that is considered to be an important component of cystic fibrosis disease. Finally, we discuss bacterial proteases, in particular, those of the most prevalent bacterial pathogen found in cystic fibrosis, Pseudomonas aeruginosa.

Fig. 1

Representation of α-, β- and γ-ENaC structures with the approximate locations of confirmed and predicted protease cleavage sites (aa amino acids, MSD membrane spanning domain). Based on figures presented in Kleyman et al. (2009), Rossier and Stutts (2009) and Hamm et al. (2010)

Fig. 2

Representation of protease activation of ENaC in airway epithelial cells. a A double-cleavage event is required for full ENaC activation (ASL airway surface liquid). The first step probably occurs by intracellular proteases (furin), followed by a second cleavage event at the surface (membrane protease). b Multiple cleavage events or a cascade of proteolysis might be involved in achieving full ENaC activation. In this scenario, ENaC is cleaved by intracellular proteases and reaches the membrane surface in either an uncleaved or partially cleaved state. It can then be further activated by membrane-bound proteases or by soluble proteases. In addition, soluble protease might initiate a cascade of proteolytic events eventually resulting in full ENaC activation. Soluble protease inhibitors and proteins that prevent ENaC cleavage (SPLUNC) might modulate the extent of ENaC activation. Images based on previous reviews (Rossier and Stutts 2009; Gaillard et al. 2010)