G-protein coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L
- Chinese Academy of Sciences, China
- Harvard Medical School, United States
- Fudan University, China
- Huazhong University of Science and Technology, China
- University of Maryland School of Medicine, United States
- University of North Carolina at Chapel Hill, United States
Abstract
Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian orthologue of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. Here we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of GPCR ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington's disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases.
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Animal experimentation: All animal experiments were carried out in accordance with an approved protocol by Shanghai Institute of Materia Medica Institutional Animal Care and Use Committee (IACUC).The protocol was approved by the research ethics committee of Chinese Academy of Sciences(Permit Number:2011-8-YQ-01).
Copyright
© 2015, Zhang 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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G-protein coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L
eLife 4:e06734.
https://doi.org/10.7554/eLife.06734
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