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

Myeongki Park, Hyun Gug Jung, Hae Jin Kweon, Yeong Eun Kim, Jae-Yong Park, Eun Mi Hwang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The bestrophin family comprises well-known Ca 2+ -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 Ca 2+ -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.

Original languageEnglish
Pages (from-to)344-350
Number of pages7
JournalBiochemical and biophysical research communications
Volume514
Issue number1
DOIs
Publication statusPublished - 2019 Jun 18

Fingerprint

Proteolysis
Ubiquitin-Protein Ligases
Ubiquitin
Tissue
Physiological Phenomena
Aminobutyrates
Chloride Channels
Retinal Pigments
Retinal Pigment Epithelium
Ubiquitination
Astrocytes
Muscle
Gastrointestinal Tract
Glutamic Acid
Brain
Degradation
Muscles

Keywords

  • BEST1
  • Chloride channel
  • E3 ubiquitin ligase
  • NEDD4L

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The E3 ubiquitin ligase, NEDD4L (NEDD4-2) regulates bestrophin-1 (BEST1) by ubiquitin-dependent proteolysis. / Park, Myeongki; Jung, Hyun Gug; Kweon, Hae Jin; Kim, Yeong Eun; Park, Jae-Yong; Hwang, Eun Mi.

In: Biochemical and biophysical research communications, Vol. 514, No. 1, 18.06.2019, p. 344-350.

Research output: Contribution to journalArticle

Park, Myeongki ; Jung, Hyun Gug ; Kweon, Hae Jin ; Kim, Yeong Eun ; Park, Jae-Yong ; Hwang, Eun Mi. / The E3 ubiquitin ligase, NEDD4L (NEDD4-2) regulates bestrophin-1 (BEST1) by ubiquitin-dependent proteolysis. In: Biochemical and biophysical research communications. 2019 ; Vol. 514, No. 1. pp. 344-350.
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