Cc. Goulet et al., INHIBITION OF THE EPITHELIAL NA-SYNDROME( CHANNEL BY INTERACTION OF NEDD4 WITH A PY MOTIF DELETED IN LIDDLES), The Journal of biological chemistry, 273(45), 1998, pp. 30012-30017
The epithelial Na+ channel (ENaC) plays a critical role in Na+ absorpt
ion in the kidney and other epithelia, Mutations in the C terminus of
the beta or gamma ENaC subunits increase renal Na+ absorption, causing
Liddle's syndrome, an inherited form of hypertension. These mutations
delete or disrupt a PY motif that was recently shown to interact with
Nedd4, a ubiquitin-protein ligase expressed in epithelia, We found th
at Nedd4 inhibited ENaC when they were coexpressed in Xenopus oocytes.
Liddle's syndrome-associated mutations that prevent the interaction b
etween Nedd4 and ENaC abolished inhibition, suggesting that a direct i
nteraction is required for inhibition by Nedd4. Inhibition also requir
ed activity of a ubiquitin ligase domain within the C terminus of Nedd
4, Nedd4 had no detectable effect on the single channel properties of
ENaC, Rather, Nedd4 decreased cell surface expression of both ENaC and
a chimeric protein containing the C terminus of the beta subunit, Dec
reased surface expression resulted from an increase in the rate of deg
radation of the channel complex. Thus, interaction of Nedd4 with the C
terminus of ENaC inhibits Na+ absorption, and loss of this interactio
n may play a role in the pathogenesis of Liddle's syndrome and other f
orms of hypertension.