COMMD1 downregulates the epithelial sodium channel through Nedd4–2

Y Ke, AG Butt, M Swart, YF Liu… - American Journal of …, 2010 - journals.physiology.org
Y Ke, AG Butt, M Swart, YF Liu, FJ McDonald
American Journal of Physiology-Renal Physiology, 2010journals.physiology.org
The epithelial sodium channel (ENaC) is important for the long-term control of Na+
homeostasis and blood pressure. Our previous studies demonstrated that Co pper M
etabolism M urr1 D omain-containing protein 1 (COMMD1; previously known as Murr1), a
protein involved in copper metabolism, inhibited amiloride-sensitive current in Xenopus
laevis oocytes expressing ENaC (J Biol Chem 279: 5429, 2004). In this study, we report that
COMMD1 inhibits amiloride-sensitive current in mammalian epithelial cells expressing …
The epithelial sodium channel (ENaC) is important for the long-term control of Na+ homeostasis and blood pressure. Our previous studies demonstrated that Copper Metabolism Murr1 Domain-containing protein 1 (COMMD1; previously known as Murr1), a protein involved in copper metabolism, inhibited amiloride-sensitive current in Xenopus laevis oocytes expressing ENaC (J Biol Chem 279: 5429, 2004). In this study, we report that COMMD1 inhibits amiloride-sensitive current in mammalian epithelial cells expressing ENaC, that the COMM domain of COMMD1 is sufficient for this effect, and that knockdown of COMMD1 increases amiloride-sensitive current. COMMD1 is coexpressed with ENaC in rat kidney medulla cells. COMMD1 increased ubiquitin modification of ENaC and decreased its cell surface expression. COMMD1 abolished insulin-stimulated amiloride-sensitive current and attenuated the stimulation of current by activated serum and glucocorticoid-regulated kinase (SGK1). COMMD1 was found to interact with both SGK1 and Akt1/protein kinase B, and knockdown of COMMD1 enhanced the stimulatory effect of both SGK1 and Akt1 on amiloride-sensitive current. COMMD1's effects were reduced in the presence of ENaC proteins containing PY motif mutations, abolished in the presence of a dominant negative form of Nedd4–2, and knockdown of COMMD1 reduced the inhibitory effect of Nedd4–2 on ENaC, but did not enhance current when Nedd4–2 was knocked down. These data suggest that COMMD1 modulates Na+ transport in epithelial cells through regulation of ENaC cell surface expression and this effect is likely mediated via Nedd4–2.
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