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FASEB J
2013 Oct 01;2710:4100-7. doi: 10.1096/fj.13-229294.
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Small GTPase Rab14 down-regulates UT-A1 urea transport activity through enhanced clathrin-dependent endocytosis.
Su H
,
Liu B
,
Fröhlich O
,
Ma H
,
Sands JM
,
Chen G
.
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The UT-A1 urea transporter plays an important role in the urinary concentration mechanism. However, the molecular mechanisms regarding UT-A1 trafficking, endocytosis, and degradation are still unclear. In this study, we identified the small GTPase Rab14 as a binding partner to the C terminus of UT-A1 in a yeast 2-hybrid assay. Interestingly, UT-A1 binding is preferential for the GDP-bound inactive form of Rab14. Coinjection of Rab14 in Xenopus oocytes results in a decrease of UT-A1 urea transport activity, suggesting that Rab14 acts as a negative regulator of UT-A1. We subsequently found that Rab14 reduces the cell membrane expression of UT-A1, as evidenced by cell surface biotinylation. This effect is blocked by chlorpromazine, an inhibitor of the clathrin-mediated endocytic pathway, but not by filipin, an inhibitor of the caveolin-mediated endocytic pathway. In kidney, Rab14 is mainly expressed in IMCD epithelial cells with a pattern identical to UT-A1 expression. Consistent with its role in participating in clathrin-mediated endocytosis, Rab14 localizes in nonlipid raft microdomains and codistributes with Rab5, a marker of the clathrin-mediated endocytic pathway. Taken together, our study suggests that Rab14, as a novel UT-A1 partner, may have an important regulatory function for UT-A1 urea transport activity in the kidney inner medulla.
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