Interaction Of COMMD Family Proteins With The Epithelial Sodium Channel.

The COMMD ( Co pper M etabolism gene M urr1 D omain) family of proteins consists of 10 members, COMMD1‐10. The prototype of the COMMD family, COMMD1, was found to be involved in copper metabolism, NF‐κB signaling and sodium uptake. The classic epithelial sodium channel (ENaC) in the distal kidney is made up of three similar subunits, α, β and γENaC subunits. Another ENaC family member, δENaC, is expressed throughout the brain. Previously our laboratory identified COMMD1 was an ENaC‐interacting protein and inhibited amiloride‐sensitive Na + transport of the δβγENaC subunits and αβγENaC channels [1]. Therefore, we hypothesized other COMMD proteins might (1) bind to ENaC, (2) regulate ENaC and (3) if other COMMD proteins do regulate ENaC activities, COMMD might be involved in the Nedd4‐2 ubiquitination pathway in the regulation of ENaC. Our GST pulldown and co‐immunoprecipitation results have shown that most COMMD proteins bound to α, β, γ and δENaC subunits. Using immunohistochemistry experiments we show that COMMD3 and COMMD9 are both expressed in kidney and overlay with αENaC expression. Functional data from Ussing chamber experiments has shown that COMMD3 and COMMD9 down‐regulate ENaC currents in FRT cells. Therefore COMMD3 and COMMD9 may be novel regulators of ENaC.