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

Abstract	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.
Authors	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
Journal	eLife (Elife) Vol. 4 Pg. e06734 (Mar 30 2015) ISSN: 2050-084X [Electronic] England
PMID	25821988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Atg14 protein, mouse Autophagy-Related Proteins Benzylamines Carrier Proteins Chromones Cul3 protein, mouse Cullin Proteins Cyclams Heterocyclic Compounds Kruppel-Like Transcription Factors Morpholines Phosphatidylinositol Phosphates Promyelocytic Leukemia Zinc Finger Protein RBX1 protein, mouse Receptors, CXCR4 Vesicular Transport Proteins Zbtb16 protein, mouse phosphatidylinositol 3-phosphate 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one Proteasome Endopeptidase Complex plerixafor
Topics	Animals Autophagy (drug effects, genetics) Autophagy-Related Proteins Benzylamines Carrier Proteins (genetics, metabolism) Cell Line, Tumor Chromones (pharmacology) Cullin Proteins (genetics, metabolism) Cyclams Disease Models, Animal Gene Expression Regulation HEK293 Cells Heterocyclic Compounds (pharmacology) Humans Huntington Disease (drug therapy, genetics, mortality, pathology) Kruppel-Like Transcription Factors (genetics, metabolism) Mice Morpholines (pharmacology) Phagosomes Phosphatidylinositol Phosphates (biosynthesis) Promyelocytic Leukemia Zinc Finger Protein Proteasome Endopeptidase Complex (drug effects, metabolism) Proteolysis (drug effects) Psychomotor Performance (drug effects) Receptors, CXCR4 (antagonists & inhibitors, genetics, metabolism) Rotarod Performance Test Signal Transduction Survival Analysis Ubiquitination Vesicular Transport Proteins (genetics, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!