Epithelial sodium channel biogenesis and quality control in the early secretory pathway

The epithelial sodium channel, ENaC, is responsible for Na reabsorption in several epithelia and is composed of homologous α, β, and γ subunits. Here, we will explore the differential regulation of ENaC subunits during biogenesis in the early secretory pathway.

ENaC subunits are subject to numerous posttranslational modifications, including glycosylation, protease activation, disulfide bond formation, palmitoylation, and glycosylation, each of which modulate channel function. For example, glycan addition is regulated by sodium and affects protease activation at the cell surface, protein trafficking, sodium-dependent regulation, and sodium transport. Glycosylation of the α subunit also determines whether a chaperone, Lhs1/GRP170, selects the protein for endoplasmic reticulum-associated degradation. Recognition by this chaperone is blocked by assembly of the ENaC transmembrane domains. In contrast, cytosolic lysines are acetylated in the early secretory pathway, which inhibits ubiquitination and endocytosis at the cell surface.

As sodium reabsorption by ENaC in the distal nephron regulates salt and water homeostasis, ENaC function is critical for human health. Therefore, identifying and characterizing modifiers of ENaC in the early secretory pathway may provide both new therapeutic targets and further our basic understanding of membrane protein assembly and regulation.