ENaC activation by proteases

Abstract

Proteases are fundamental for a plethora of biological processes, including signalling and tissue remodelling, and dysregulated proteolytic activity can result in pathogenesis. In this review, we focus on a subclass of membrane‐bound and soluble proteases that are defined as channel‐activating proteases (CAPs), since they induce Na+ ion transport through an autocrine mechanism when co‐expressed with the highly amiloride‐sensitive epithelial sodium channel (ENaC) in Xenopus oocytes. These experiments first identified CAP1 (channel‐activating protease 1, prostasin) followed by CAP2 (channel‐activating protease 2, TMPRSS4) and CAP3 (channel‐activating protease 3, matriptase) as in vitro mediators of ENaC current. Since then, more serine‐, cysteine‐ and metalloproteases were confirmed as in vitro CAPs that potentially cleave and regulate ENaC, and thus this nomenclature was not further followed, but is accepted as functional term or alias. The precise mechanism of ENaC modulation by proteases has not been fully elucidated. Studies in organ‐specific protease knockout models revealed evidence for their role in increasing ENaC activity, although the proteases responsible for ENaC activation are yet to be identified. We summarize recent findings in animal models of these CAPs with respect to their implication in ENaC activation. We discuss the consequences of dysregulated CAPs underlying epithelial phenotypes in pathophysiological conditions, and the role of selected protease inhibitors. We believe that these proteases may present interesting therapeutic targets for diseases with aberrant sodium homoeostasis.

COVID-19 and Liquid Homeostasis in the Lung—A Perspective through the Epithelial Sodium Channel (ENaC) Lens

“…Furthermore, the cleavage sites in γ ENaC can be cleaved by more than one protease [ 36 ]. Moreover, to add more complexity, there are intracellular proteases (e.g., furin) and extracellular proteases (e.g., CAP1), with some of the latter being either membrane-anchored or secreted to be freely available in the extracellular space [ 37 ].…”

“…The recent understanding is that fully activated ENaC comprises an α subunit that is cleaved twice by the protease furin during the transition through the trans-Golgi network and a γ subunit that is also cleaved once by furin in the trans-Golgi network and another protease at the cell membrane (e.g., CAP1) [ 37 , 38 , 39 ]. The proteolytic cleavage of the subunits can be sequential and occur in various locations (intra- and extracellularly), and this is suggested to provide opportunities for a graduate activation and regulation [ 39 ].…”

Rodent models to study sodium retention in experimental nephrotic syndrome

“…Among the redundant regulatory mechanism, proteolytic processing is a unique feature of ENaC, leading to the removal of inhibitory peptide tracts from the αand γsubunits by serine proteases. [98][99][100][101][102][103][104] After intracellular cleavage at two sites in α-ENaC and one in γ-ENaC during channel maturation in the trans-Golgi network by the serine protease furin, final proteolytic ENaC activation takes place at the plasma membrane where γ-ENaC is cleaved by membrane-bound proteases such as prostasin 105 and/ or other extracellular proteases in a region C-terminal to the furin site. [98][99][100][101][102][103][104] During proteolytic processing, the open probability of ENaC increases and reaches almost 100% in the fully cleaved state.…”

“…[98][99][100][101][102][103][104] After intracellular cleavage at two sites in α-ENaC and one in γ-ENaC during channel maturation in the trans-Golgi network by the serine protease furin, final proteolytic ENaC activation takes place at the plasma membrane where γ-ENaC is cleaved by membrane-bound proteases such as prostasin 105 and/ or other extracellular proteases in a region C-terminal to the furin site. [98][99][100][101][102][103][104] During proteolytic processing, the open probability of ENaC increases and reaches almost 100% in the fully cleaved state. 103 Nephrotic syndrome leads to aberrant filtration of serine proteases from the plasma, such as plasmin, 16 into the urine.…”

Kidney-Specific CAP1/Prss8-Deficient Mice Maintain ENaC-Mediated Sodium Balance through an Aldosterone Independent Pathway

“…CAP1/Prss8 (and its human orthologue prostasin) was the first protease shown to activate ENaC in vitro. This was followed by more members of the subfamily of membrane-bound serine proteases such as CAP2/Tmprss4 and CAP3/St14 (matriptase), and also intracellular or soluble serine proteases, like furin, elastase, kallikrein and plasmin as well as the metalloproteinase meprin or the lysosomal cysteine protease cathepsin-S [ 3 , 4 ]. In kallikrein-deficient mice, defective ENaC processing and function was documented in kidney cortex suggesting that the renal kallikrein-kinin system may play a role in Na + balance and blood pressure regulation [ 5 ].…”