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E3 ligase MDM2 mediates urea transporter A1 ubiquitination under either constitutive or stimulatory conditions.

Su, Hua; Ye, Chen; Sands, Jeff M; Zhang, Chun.
Artigo em Inglês | MEDLINE | ID: mdl-31509007
Post-translational modifications are essential for regulation of the urea transporter A1 (UT-A1), among which ubiquitination is a rather attractive and complex issue. Earlier, our group reported that MDM2 is one of E3 ubiquitin ligases for UT-A1, and later we showed that ubiquitination contributes to the subcellular trafficking and stability of UT-A1. In the current study, we discovered that MDM2 interacts with UT-A1 in an AP50, a component of the clathrin-coated pit, dependent manner. But their binding is irrelevant to the phosphorylatory status of UT-A1. Next, our findings indicated that MDM2 decreases the stability of either total or membrane UT-A1. On the cell membrane, MDM2 and ubiquitinated UT-A1 are both distributed in the lipid raft domain, and their linkage is obviously enhanced under forskolin (FSK) stimulation. In line with these results, in diabetic rat not only MDM2 but also ubiquitinated UT-A1 are intensified. Also, in vitro high glucose and angiotensin Ⅱ play similar roles as FSK does on the association of MDM2 with UT-A1. In conclusion, MDM2 binds with UT-A1 and mediates its ubiquitination and degradation in an AP50 dependent manner, and their binding capacity is strengthened under FSK and diabetic milieu.
Selo DaSilva