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CF airways exhibit ion transport abnormalities, including hyperactivity of the epithelial Na\n                    <jats:sup>+<\/jats:sup>\n                    channel (ENaC). Short\u2010palate lung and nasal epithelial clone 1 (SPLUNC1) is a multifunctional innate defense protein that is secreted into the airway lumen. We have previously demonstrated that SPLUNC1 binds to and inhibits ENaC to maintain fluid homeostasis in airway epithelia and that this process fails in CF airways. Despite this, how SPLUNC1 actually regulates ENaC is unknown. Here, we found that SPLUNC1 caused \u03b1\u03b3\u2010ENaC to internalize, whereas SPLUNC1 and \u03b2\u2010ENaC remained at the plasma membrane. Additional studies revealed that SPLUNC1 increased neural precursor cell\u2010expressed developmentally down\u2010regulated protein 4\u20132\u2010dependent ubiquitination of \u03b1\u2010 but not \u03b2\u2010 or \u03b3\u2010ENaC. We also labeled intracellular ENaC termini with green fluorescent protein and mCherry, and found that extracellular SPLUNC1 altered intracellular ENaC Forster resonance energy transfer. Taken together, our data indicate that SPLUNC1 is an allosteric regulator of ENaC that dissociates abg\u2010ENaC to generate a new SPLUNC1\u2013 \u03b2\u2010ENaC complex. These data indicate a novel mode for regulating ENaC at the plasma membrane.\u2014Kim, C. S., Ahmad, S., Wu, T., Walton, W. G., Redinbo, M. R., Tarran, R. SPLUNC1 is an allosteric modulator of the epithelial sodium channel. 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