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

• Published in: eLife 2015-03, Vol.4, p.e06734-e06734
• Main Authors: Zhang, Tao, Dong, Kangyun, Liang, Wei, Xu, Daichao, Xia, Hongguang, Geng, Jiefei, Najafov, Ayaz, Liu, Min, Li, Yanxia, Han, Xiaoran, Xiao, Juan, Jin, Zhenzhen, Peng, Ting, Gao, Yang, Cai, Yu, Qi, Chunting, Zhang, Qing, Sun, Anyang, Lipinski, Marta, Zhu, Hong, Xiong, Yue, Pandolfi, Pier Paolo, Li, He, Yu, Qiang, Yuan, Junying
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Autophagy - drug effects; Autophagy - genetics; Autophagy-Related Proteins; Biodegradation; Biology; Cancer; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Biology; Cell Line, Tumor; Central nervous system; Chromones - pharmacology; Cullin Proteins - genetics; Cullin Proteins - metabolism; Disease Models, Animal; G protein-coupled receptors; Gene Expression Regulation; GPCR; HEK293 Cells; Heterocyclic Compounds - pharmacology; Humans; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - mortality; Huntington Disease - pathology; Huntington's disease; Immunoglobulins; Kinases; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Laboratories; Ligands; Medical research; Mice; Morpholines - pharmacology; Nervous system; Neurodegenerative diseases; Phagocytosis; Phagosomes; Phosphatidylinositol Phosphates - biosynthesis; Promyelocytic Leukemia Zinc Finger Protein; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein folding; Proteins; Proteolysis - drug effects; Psychomotor Performance - drug effects; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Rotarod Performance Test; Signal Transduction; Statistical analysis; Survival Analysis; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.06734

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.