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.
Keywords:
GPCR; autophagy; cell biology; mouse; ubiquitination.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autophagy / drug effects
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Autophagy / genetics
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Autophagy-Related Proteins
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Benzylamines
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line, Tumor
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Chromones / pharmacology
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Cullin Proteins / genetics
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Cullin Proteins / metabolism
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Cyclams
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Disease Models, Animal
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Gene Expression Regulation
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HEK293 Cells
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Heterocyclic Compounds / pharmacology*
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Humans
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Huntington Disease / drug therapy*
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Huntington Disease / genetics*
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Huntington Disease / mortality
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Huntington Disease / pathology
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Kruppel-Like Transcription Factors / genetics*
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Morpholines / pharmacology
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Phagosomes
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Phosphatidylinositol Phosphates / biosynthesis
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Promyelocytic Leukemia Zinc Finger Protein
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Endopeptidase Complex / metabolism
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Proteolysis / drug effects
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Psychomotor Performance / drug effects
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Receptors, CXCR4 / antagonists & inhibitors
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Receptors, CXCR4 / genetics*
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Receptors, CXCR4 / metabolism
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Rotarod Performance Test
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Signal Transduction
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Survival Analysis
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Ubiquitination
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Vesicular Transport Proteins / genetics*
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Vesicular Transport Proteins / metabolism
Substances
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Atg14 protein, mouse
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Autophagy-Related Proteins
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Benzylamines
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Carrier Proteins
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Chromones
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Cul3 protein, mouse
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Cullin Proteins
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Cyclams
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Heterocyclic Compounds
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Kruppel-Like Transcription Factors
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Morpholines
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Phosphatidylinositol Phosphates
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Promyelocytic Leukemia Zinc Finger Protein
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RBX1 protein, mouse
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Receptors, CXCR4
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Vesicular Transport Proteins
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Zbtb16 protein, mouse
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phosphatidylinositol 3-phosphate
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Proteasome Endopeptidase Complex
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plerixafor