The delta subunit of the epithelial sodium channel (delta ENaC) is a member of the ENaC/degenerin family of ion channels. delta ENaC is distinct from the related alpha-, beta- and gamma ENaC subunits, known for their role in sodium homeostasis and blood pressure control, as delta ENaC is expressed in brain neurons and activated by external protons. COMMD1 (copper metabolism Murr1 domain 1) was previously found to associate with and downregulate delta ENaC activity. Here, we show that COMMD1 interacts with delta ENaC through its COMM domain. Co-expression of delta ENaC with COMMD1 significantly reduced delta ENaC surface expression, and led to an increase in delta ENaC ubiquitination. Immunocytochemical and confocal microscopy studies show that COMMD1 promoted localization of delta ENaC to the early/recycling endosomal pool where the two proteins were localized together. These results suggest that COMMD1 downregulates delta ENaC activity by reducing delta ENaC surface expression through promoting internalization of surface delta ENaC to an intracellular recycling pool, possibly via enhanced ubiquitination. (C) 2011 Elsevier Inc. All rights reserved.