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Down-regulation of intestinal apical calcium entry channel TRPV6 by ubiquitin E3 ligase Nedd4-2 Zhang W; Na T; Wu G; Jing H; Peng JBJ Biol Chem 2010[Nov]; 285 (47): 36586-96Nedd4-2 is an archetypal HECT ubiquitin E3 ligase that disposes target proteins for degradation. Because of the proven roles of Nedd4-2 in degradation of membrane proteins, such as epithelial Na(+) channel, we examined the effect of Nedd4-2 on the apical Ca(2+) channel TRPV6, which is involved in transcellular Ca(2+) transport in the intestine using the Xenopus laevis oocyte system. We demonstrated that a significant amount of Nedd4-2 protein was distributed to the absorptive epithelial cells in ileum, cecum, and colon along with TRPV6. When co-expressed in oocytes, Nedd4-2 and, to a lesser extent, Nedd4 down-regulated the protein abundance and Ca(2+) influx of TRPV6 and TRPV5, respectively. TRPV6 ubiquitination was increased, and its stability was decreased by Nedd4-2. The Nedd4-2 inhibitory effects on TRPV6 were partially blocked by proteasome inhibitor MG132 but not by the lysosome inhibitor chloroquine. The rate of TRPV6 internalization was not significantly altered by Nedd4-2. The HECT domain was essential to the inhibitory effect of Nedd4-2 on TRPV6 and to their association. The WW1 and WW2 domains interacted with TRPV6 terminal regions, and a disruption of the interactions by D204H and D376H mutations in the WW1 and WW2 domains increased TRPV6 ubiquitination and degradation. Thus, WW1 and WW2 may serve as a molecular switch to limit the ubiquitination of TRPV6 by the HECT domain. In conclusion, Nedd4-2 may regulate TRPV6 protein abundance in intestinal epithelia by controlling TRPV6 ubiquitination.|Animals[MESH]|Blotting, Western[MESH]|Calcium Channels/chemistry/genetics/*metabolism[MESH]|Calcium/*metabolism[MESH]|Down-Regulation[MESH]|Endosomal Sorting Complexes Required for Transport/genetics/*metabolism[MESH]|Humans[MESH]|Immunoprecipitation[MESH]|Intestinal Mucosa/*metabolism[MESH]|Intestines/cytology[MESH]|Nedd4 Ubiquitin Protein Ligases[MESH]|Oocytes/cytology/physiology[MESH]|RNA, Messenger/genetics[MESH]|Rats[MESH]|Reverse Transcriptase Polymerase Chain Reaction[MESH]|TRPV Cation Channels/chemistry/genetics/*metabolism[MESH]|Ubiquitin-Protein Ligases/genetics/*metabolism[MESH]|Ubiquitin/*metabolism[MESH]|Ubiquitination[MESH]|Xenopus Proteins[MESH]|Xenopus laevis[MESH] |
