title: 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.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Kangyun
authors.initials: K
authors.lastname: Dong
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Daichao
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Hongguang
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Jiefei
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Ayaz
authors.initials: A
authors.lastname: Najafov
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Li
authors.affiliation: Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Han
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Peng
authors.affiliation: Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Chunting
authors.initials: C
authors.lastname: Qi
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Anyang
authors.initials: A
authors.lastname: Sun
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Marta
authors.initials: M
authors.lastname: Lipinski
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Department of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071183:Autophagy-Related Proteins; D001596:Benzylamines; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D000080027:Cyclams; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D010588:Phagosomes; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D045442:Rotarod Performance Test; D015398:Signal Transduction; D016019:Survival Analysis; D054875:Ubiquitination; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C561107:Atg14 protein, mouse; D000071183:Autophagy-Related Proteins; D001596:Benzylamines; D002352:Carrier Proteins; D002867:Chromones; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D000080027:Cyclams; D006571:Heterocyclic Compounds; D051741:Kruppel-Like Transcription Factors; D009025:Morpholines; D018129:Phosphatidylinositol Phosphates; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C540494:RBX1 protein, mouse; D019718:Receptors, CXCR4; D033921:Vesicular Transport Proteins; C513267:Zbtb16 protein, mouse; C055525:phosphatidylinositol 3-phosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D046988:Proteasome Endopeptidase Complex; C088327:plerixafor
keywords: GPCR; autophagy; cell biology; mouse; ubiquitination
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