The E3 ubiquitin ligase, NEDD4L (NEDD4-2) regulates bestrophin-1 (BEST1) by ubiquitin-dependent proteolysis

Title
The E3 ubiquitin ligase, NEDD4L (NEDD4-2) regulates bestrophin-1 (BEST1) by ubiquitin-dependent proteolysis
Authors
황은미정현국김영은Myeongki ParkHae-Jin KweonJae-Yong Park
Issue Date
2019-06
Publisher
Biochemical and biophysical research communications
Citation
VOL 514, NO 1-350
Abstract
The bestrophin family comprises well-known Ca2+-activated chloride channels (CaCC) that are expressed in a variety tissues including the brain, eye, gastrointestinal tract, and muscle tissues. Among the family members, bestrophin-1 (BEST1) is known to exist mainly in retinal pigment epithelium cells, but we recently reported that BEST1 mediates Ca2+-activated Cl− currents in hippocampal astrocytes. Despite its critical roles in physiological processes, including tonic γ-aminobutyric acid release and glutamate transport, the mechanisms that regulate BEST1 are poorly understood. In this study, we identified NEDD4L (NEDD4-2), an E3 ubiquitin ligase, as a binding partner of BEST1. A series of deletion constructs revealed that the WW3-4 domains of NEDD4L were important for interaction with BEST1. We observed that BEST1 underwent ubiquitin-dependent proteolysis and found that the conserved lysine370 residue in the C-terminus of BEST1 was important for its ubiquitination. Finally, we demonstrated that NEDD4L inhibited whole cell currents mediated by BEST1 but not by the BEST1(K370R) mutant. Collectively, our data demonstrated that NEDD4L played a critical role in regulating the surface expression of BEST1 by promoting its internalization and degradation.
URI
http://pubs.kist.re.kr/handle/201004/69365
ISSN
0006-291X
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