Abstract
The epithelial Na+channel ENaC forms a pathway for Na+ absorption across epithelia. Various proteases regulate ENaC by altering its activity. Here we tested the effect of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) on ENaC. We found that PCSK9 and ENaC interact using a coimmunoprecipitation assay. PCSK9 decreased amiloride sensitive Na+ current in Xenopus oocytes and in FRT epithelia expressing αβγENaC. This resulted from decreased ENaC cell surface expression. Using a cycloheximide chase assay we found that PCSK9 accelerated degradation of ENaC. The proteasomal inhibitor ALLN reversed this decrease in ENaC protein. In contrast, PCSK9 had no effect on endocytosis or degradation of the cell surface pool of ENaC. Together, the data indicate that PCSK9 regulates ENaC by increasing its degradation in the biosynthetic pathway.Supported by funding from American Heart Association 0920147G (VS) and NIH HL058812 (PMS)
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