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Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel

¹Department of Internal Medicine, ²Graduate Program in Molecular Biology, University of Iowa College of Medicine and ³Veterans Affairs Medical Center, Iowa City, Iowa

Submitted 19 July 2007 ; accepted in final form 3 March 2008

We previously reported the existence of multiple isoforms of human Nedd4-2 (Am J Physiol Renal Physiol 285: F916–F929, 2003). When overexpressed in M-1 collecting duct epithelia, full-length Nedd4-2 (Nedd4-2), Nedd4-2 lacking the NH₂-terminal C2 domain (Nedd4-2C2), and Nedd4-2 lacking WW domains 2 and 3 (Nedd4-2WW2,3) variably reduce benzamil-sensitive Na⁺ transport. We investigated the effect of each of the Nedd4-2 isoforms on cell surface expression and ubiquitination of ENaC subunits. We find that ENaC when transfected alone or with β and ENaC is expressed at the cell surface and this membrane expression is variably reduced by coexpression with each of the Nedd4-2 isoforms. Nedd4-2 reduces the half-life of ENaC subunits and enhances the ubiquitination of , β, and ENaC subunits when expressed alone or together suggesting that each subunit is a target for Nedd4-2-mediated ubiquitination. As has been reported recently, we confirm that the surface-expressed pool of ENaC is multi-ubiquitinated. Inhibitors of the proteasome increase ubiquitination of ENaC subunits and stimulate Na⁺ transport in M-1 cells consistent with a role for the ubiquitin-proteasome pathway in regulating Na⁺ transport in the collecting duct.

sodium transport; collecting duct; hypertension

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