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The epithelial sodium channel (ENaC) has an important role in maintaining salt and water balance, and in long-term blood pressure control. Multiple proteins interact with ENaC to control its forward movement along the protein secretion pathway to the cell surface, and ENaC endocytosis and trafficking to the lysosome or recycling endosome (reviewed in Butterworth 2010). For example, the E3 ubiquitin ligase Nedd4-2 catalyses covalent attachment of ubiquitin moieties onto ENaC subunits to promote endocytosis and trafficking to the lysosome. Nedd4-2 action is mitigated upon its phosphorylation by the aldosterone-stimulated kinase SGK1. The regulation of ENaC in the kidney by Nedd4-2 and SGK1 appears to be a key pathway by which ENaC Na+ transport is controlled. We discovered that the Copper Metabolism Murr1 Domain-containing protein 1 (COMMD1) interacts with ENaC (Biasio et al., 2004), and reduces amiloride-sensitive short circuit current (Isc-amil) in Fischer rat thyroid (FRT) epithelia expressing ENaC. COMMD1 appears to form a complex with SGK-Nedd4-2 resulting in a decrease in the ENaC population at the cell surface (Ke etal.,2010).COMMD1 is the founding member of a ten-member family of proteins (COMMD1-10) sharing a C-terminal COMM domain (Burstein et al., 2005). Although COMMD1 has pleiotropic roles in copper, chloride transport, NF-κBtranscriptional downregulation, and regulation of the HIF1α complex, roles for other COMMD proteins have not been described. To investigate whether other COMMD proteins also regulate ENaC we used co-immunoprecipitation and showed that COMMD1-10 all interact with ENaC. Using immunohistochemistry we found that COMMD1, 3, and 9 were widely expressed in rat kidney including collecting duct cells, and showed colocalisation with ENaC. COMMD1, 3, and 9 individually inhibited Isc-amil in ENaC-expressing FRT epithelia. These COMMD proteins appear to have unique roles in inhibiting ENaC because COMMD3 and 9 retained their ability to reduce Isc-amil in ENaC-expressing FRT epithelia when COMMD1 expression was reduced using siRNA knockdown. COMMD1, 3, and 9 all decreased cell surface expression of ENaC, therefore they likely affect trafficking of ENaC to or from the cell surface. Another family member, COMMD10, was found to regulate forward trafficking of proteins in the secretory pathway. Thus multiple COMMD family members negatively regulate ENaC, but may act at different locations in the protein trafficking pathway. [ABSTRACT FROM AUTHOR]