G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L
Tao Zhang,
Kangyun Dong,
Wei Liang,
Daichao Xu,
Hongguang Xia,
Jiefei Geng,
Ayaz Najafov,
Min Liu,
Yanxia Li,
Xiaoran Han,
Juan Xiao,
Zhenzhen Jin,
Ting Peng,
Yang Gao,
Yu Cai,
Chunting Qi,
Qing Zhang,
Anyang Sun,
Marta Lipinski,
Hong Zhu,
Yue Xiong,
Pier Paolo Pandolfi,
He Li,
Qiang Yu,
Junying Yuan
Affiliations
Tao Zhang
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Kangyun Dong
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Wei Liang
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Daichao Xu
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Hongguang Xia
Department of Cell Biology, Harvard Medical School, Boston, United States
Jiefei Geng
Department of Cell Biology, Harvard Medical School, Boston, United States
Ayaz Najafov
Department of Cell Biology, Harvard Medical School, Boston, United States
Min Liu
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Yanxia Li
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Xiaoran Han
Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
Juan Xiao
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Zhenzhen Jin
Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Ting Peng
Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Yang Gao
Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Yu Cai
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Chunting Qi
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Qing Zhang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Anyang Sun
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Marta Lipinski
Department of Cell Biology, Harvard Medical School, Boston, United States
Hong Zhu
Department of Cell Biology, Harvard Medical School, Boston, United States
Yue Xiong
Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
Pier Paolo Pandolfi
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
He Li
Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Qiang Yu
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Junying Yuan
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; Department of Cell Biology, Harvard Medical School, Boston, United States
Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian ortholog 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. In this study, 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 G-protein-coupled receptor (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.
