G-protein coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L

  1. Tao Zhang
  2. Kangyun Dong
  3. Wei Liang
  4. Daichao Xu
  5. Hongguang Xia
  6. Jiefei Geng
  7. Ayaz Najafov
  8. Min Liu
  9. Yanxia Li
  10. Xiaoran Han
  11. Juan Xiao
  12. Zhenzhen Jin
  13. Ting Peng
  14. Yang Gao
  15. Yu Cai
  16. Chunting Qi
  17. Qing Zhang
  18. Anyang Sun
  19. Marta Lipinski
  20. Hong Zhu
  21. Yue Xiong
  22. Pier Paolo Pandolfi
  23. He Li
  24. Qiang Yu
  25. Junying Yuan  Is a corresponding author
  1. Chinese Academy of Sciences, China
  2. Harvard Medical School, United States
  3. Fudan University, China
  4. Huazhong University of Science and Technology, China
  5. University of Maryland School of Medicine, United States
  6. 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.

Article and author information

Author details

  1. Tao Zhang

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Kangyun Dong

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Wei Liang

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Daichao Xu

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Hongguang Xia

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jiefei Geng

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ayaz Najafov

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Min Liu

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yanxia Li

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Xiaoran Han

    Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Juan Xiao

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Zhenzhen Jin

    Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Ting Peng

    Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Yang Gao

    Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Yu Cai

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Chunting Qi

    Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  17. Qing Zhang

    Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Anyang Sun

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  19. Marta Lipinski

    Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Hong Zhu

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Yue Xiong

    Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Pier Paolo Pandolfi

    Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. He Li

    Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  24. Qiang Yu

    Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  25. Junying Yuan

    Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    For correspondence
    jyuan@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

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).

Reviewing Editor

  1. Noboru Mizushima, The University of Tokyo, Japan

Publication history

  1. Received: January 28, 2015
  2. Accepted: March 27, 2015
  3. Accepted Manuscript published: March 30, 2015 (version 1)
  4. Version of Record published: May 6, 2015 (version 2)

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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  1. Tao Zhang
  2. Kangyun Dong
  3. Wei Liang
  4. Daichao Xu
  5. Hongguang Xia
  6. Jiefei Geng
  7. Ayaz Najafov
  8. Min Liu
  9. Yanxia Li
  10. Xiaoran Han
  11. Juan Xiao
  12. Zhenzhen Jin
  13. Ting Peng
  14. Yang Gao
  15. Yu Cai
  16. Chunting Qi
  17. Qing Zhang
  18. Anyang Sun
  19. Marta Lipinski
  20. Hong Zhu
  21. Yue Xiong
  22. Pier Paolo Pandolfi
  23. He Li
  24. Qiang Yu
  25. Junying Yuan
(2015)
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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