Downregulation of urea transporter UT-A1 activity by 14-3-3 protein

作者：Feng Xiuyan; Li Zenggang; Du Yuhong; Fu Haian; Klein Janet D; Cai Hui; Sands Jeff M; Chen Guangping^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2015, 309(1): F71-F78.

DOI：10.1152/ajprenal.00546.2014

• protein kinase A
• accessory protein
• protein turnover
• urea transporter

Urea transporter (UT)-A1 in the kidney inner medulla plays a critical role in the urinary concentrating mechanism and thereby in the regulation of water balance. The 14-3-3 proteins are a family of seven isoforms. They are multifunctional regulatory proteins that mainly bind to phosphorylated serine/threonine residues in target proteins. In the present study, we found that all seven 14-3-3 isoforms were detected in the kidney inner medulla. However, only the 14-3-3 gamma-isoform was specifically and highly associated with UT-A1, as demonstrated by a glutathione-S-transferase-14-3-3 pulldown assay. The cAMP/adenylyl cyclase stimulator forskolin significantly enhanced their binding. Coinjection of 14-3-3 gamma cRNA into oocytes resulted in a decrease of UT-A1 function. In addition, 14-3-3 gamma increased UT-A1 ubiquitination and protein degradation. 14-3-3 gamma can interact with both UT-A1 and mouse double minute 2, the E3 ubiquitin ligase for UT-A1. Thus, activation of cAMP/PKA increases 14-3-3 gamma interactions with UT-A1 and stimulates mouse double minute 2-mediated UT-A1 ubiquitination and degradation, thereby forming a novel regulatory mechanism of urea transport activity.

• 出版日期2015-7-1