Regulation of Epithelial Sodium Channel Trafficking by Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

• Published in: The Journal of biological chemistry Vol. 287; no. 23; pp. 19266 - 19274
• Main Authors: Sharotri, Vikas, Collier, Daniel M., Olson, Diane R., Zhou, Ruifeng, Snyder, Peter M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Blood Pressure - physiology; ENaC; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelial Sodium Channels - biosynthesis; Epithelial Sodium Channels - genetics; Epithelium; ER-associated Degradation; HEK293 Cells; Humans; Ion Channels; Ion Transport - physiology; Membrane Biology; Proprotein Convertase 9; Proprotein Convertases - genetics; Proprotein Convertases - metabolism; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Protein Stability; Protein Transport - physiology; Proteolysis; Receptors, LDL - genetics; Receptors, LDL - metabolism; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Sodium - metabolism; Xenopus laevis; ENaC; Protein Stability; Ion Channels; Epithelium; ER-associated Degradation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.363382

The epithelial Na+ channel (ENaC) is critical for Na+ homeostasis and blood pressure control. Defects in its regulation cause inherited forms of hypertension and hypotension. Previous work found that ENaC gating is regulated by proteases through cleavage of the extracellular domains of the α and γ subunits. Here we tested the hypothesis that ENaC is regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9), a protease that modulates the risk of cardiovascular disease. PCSK9 reduced ENaC current in Xenopus oocytes and in epithelia. This occurred through a decrease in ENaC protein at the cell surface and in the total cellular pool, an effect that did not require the catalytic activity of PCSK9. PCSK9 interacted with all three ENaC subunits and decreased their trafficking to the cell surface by increasing proteasomal degradation. In contrast to its previously reported effects on the LDL receptor, PCSK9 did not alter ENaC endocytosis or degradation of the pool of ENaC at the cell surface. These results support a role for PCSK9 in the regulation of ENaC trafficking in the biosynthetic pathway, likely by increasing endoplasmic reticulum-associated degradation. By reducing ENaC channel number, PCSK9 could modulate epithelial Na+ absorption, a major contributor to blood pressure control. The epithelial Na+ channel ENaC functions as a pathway for Na+ absorption across epithelia. PCSK9 reduced ENaC expression at the cell surface by enhancing its proteasomal degradation. PCSK9 inhibits ENaC-mediated Na+ absorption. These findings provide new insights into mechanisms that regulate Na+ homeostasis and blood pressure.