Nedd4 E3 ligase and beta-arrestins regulate ubiquitination, trafficking, and stability of the mGlu7 receptor
- Seoul National University College of Medicine, Korea (South), Republic of
- Seoul National University Hospital, Korea (South), Republic of
Abstract
The metabotropic glutamate receptor 7 (mGlu7) is a class C G protein-coupled receptor that modulates excitatory neurotransmitter release at the presynaptic active zone. Although post-translational modification of cellular proteins with ubiquitin is a key molecular mechanism governing protein degradation and function, mGlu7 ubiquitination and its functional consequences have not been elucidated yet. Here, we report that Nedd4 ubiquitin E3 ligase and b-arrestins regulate ubiquitination of mGlu7 in heterologous cells and rat neurons. Upon agonist stimulation, b-arrestins recruit Nedd4 to mGlu7 and facilitate Nedd4-mediated ubiquitination of mGlu7. Nedd4 and b-arrestins regulate constitutive and agonist-induced endocytosis of mGlu7 and are required for mGlu7-dependent MAPK signaling in neurons. In addition, Nedd4-mediated ubiquitination results in the degradation of mGlu7 by both the ubiquitin-proteasome system and the lysosomal degradation pathway. These findings provide a model in which Nedd4 and b-arrestin act together as a complex to regulate mGlu7 surface expression and function at presynaptic terminals.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3, 5, 6, and 7.
Article and author information
Author details
Funding
National Research Foundation (NRF-2016R1D1A1B03930951)
- Sanghyeon Lee
- Sunha Park
- Hyojin Lee
- Seulki Han
- Jae-man Song
- Young Ho Suh
National Research Foundation of Korea (NRF-2017M3C7A1029611)
- Sanghyeon Lee
- Sunha Park
- Hyojin Lee
- Seulki Han
- Jae-man Song
- Young Ho Suh
National Research Foundation of Korea (2018R1A2B6004759)
- Sanghyeon Lee
- Sunha Park
- Jae-man Song
- Young Ho Suh
Korea Health Industry Development Institute (HI18C0789)
- Sanghyeon Lee
- Sunha Park
- Jae-man Song
- Young Ho Suh
Seoul National University Hospital Research fund (0320150260)
- Sanghyeon Lee
- Sunha Park
- Hyojin Lee
- Seulki Han
- Jae-man Song
- Young Ho Suh
Cooperative research program from Seoul National University College of Medicine (800-20180195)
- Sanghyeon Lee
- Sunha Park
- Jae-man Song
- Young Ho Suh
Brain Korea 21 PLUS program
- Sanghyeon Lee
- Sunha Park
- Hyojin Lee
- Seulki Han
- Jae-man Song
- Young Ho Suh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Seoul National University. All of the animals were handled according to approved protocol under the guidelines of the Seoul National University Institutional Animal Care and Use Committees (Approval Number: SNU-161222-2-2). The animals were sacrified by CO2 asphyxiation, and every effort was made to minimize suffering.
Copyright
© 2019, Lee et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Nedd4 E3 ligase and beta-arrestins regulate ubiquitination, trafficking, and stability of the mGlu7 receptor
eLife 8:e44502.
https://doi.org/10.7554/eLife.44502
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