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

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. DOI: http://dx.doi.org/10.7554/eLife.06734.001

• Publication year

  2015

• Venue

  eLife

• Publication date

  2015-03-30

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.7554/elife.06734.018PMID 25821988PMCID 4421748
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Endothelin receptor signaling: new insight into its regulatory mechanisms.

  2013cited by this paper
• BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs

  2012cited by this paper
• F-box protein FBXL19–mediated ubiquitination and degradation of the receptor for IL-33 limits pulmonary inflammation

  2012cited by this paper
• Atg14: A Key Player in Orchestrating Autophagy

  2011cited by this paper
• Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L)

  2011influential reference
• Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L

  2010influential reference
• A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions.

  2010influential reference
• G protein-coupled receptors: novel targets for drug discovery in cancer

  2010cited by this paper
• Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1–phosphatidylinositol-3-kinase complex

  2009cited by this paper
• Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages

  2009cited by this paper
• Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG.

  2008cited by this paper
• Structural diversity of G protein-coupled receptors and significance for drug discovery

  2008cited by this paper
• Cyclin-dependent kinase antagonizes promyelocytic leukemia zinc-finger through phosphorylation

  2008cited by this paper
• Structural diversity of G protein-coupled receptors and significance for drug discovery

  2008cited by this paper
• A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein

  2007cited by this paper
• Glycogen synthase kinase 3: A key regulator of cellular fate

  2007cited by this paper
• Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

  2006cited by this paper
• Developmental cell biology: G proteins in development

  2005cited by this paper
• Function and regulation of cullin–RING ubiquitin ligases

  2005cited by this paper
• Identification of substrates for F-box proteins.

  2005cited by this paper
• International Union of Pharmacology. XLVI. G Protein-Coupled Receptor List

  2005cited by this paper
• Targeting of protein ubiquitination by BTB–Cullin 3–Roc1 ubiquitin ligases

  2003influential reference
• BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3

  2003influential reference
• BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases.

  2003influential reference
• GSK3 takes centre stage more than 20 years after its discovery.

  2001cited by this paper
• Plzf regulates limb and axial skeletal patterning

  2000cited by this paper
• Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin.

  1999influential reference
• AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor

  1998cited by this paper
• Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex

  1996influential reference
• The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry

  1996influential reference
• Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation.

  1994cited by this paper
• Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling.

  1993cited by this paper

• Lnc-USP28-6/ZBTB16 axis orchestrates NLRP3 inflammasome activation and α-synuclein SUMOylation to drive Parkinson's disease pathogenesis.

  2026cites this paper
• Mammalian innate antiviral defenses: beyond interferon

  2025cites this paper
• The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression

  2025influential citation
• Cell- and sex-specificity in the transcriptomic response of the hippocampal neurovascular unit to obesity

  2025cites this paper
• Old versus new: upstream and downstream of promyelocytic leukemia zinc finger protein

  2025influential citation
• USP1 promotes pancreatic cancer progression and autophagy by deubiquitinating ATG14

  2025cites this paper
• A depression-associated protein FKBP5 functions in autophagy initiation through scaffolding the VPS34 complex

  2025cites this paper
• Identifying Potential Autophagy Modulators in Panch Phoron Spices (P5S): An In Silico approach

  2025cites this paper
• The Circulating Methylome in Childhood-Onset Inflammatory Bowel Disease

  2024cites this paper
• Ubiquitination regulates autophagy in cancer: simple modifications, promising targets

  2024cites this paper
• ZBTB16 inhibits DNA replication and induces cell cycle arrest by targeting WDHD1 transcription in lung adenocarcinoma

  2024cites this paper
• Identification of E3 ubiquitin ligase-associated prognostic genes and construction of a prediction model for uterine cervical cancer based on bioinformatics analysis

  2024cites this paper
• An Overview of the Unfolded Protein Response (UPR) and Autophagy Pathways in Human Viral Oncogenesis.

  2024cites this paper
• To Kill or to Be Killed: How Does the Battle between the UPS and Autophagy Maintain the Intracellular Homeostasis in Eukaryotes?

  2023cites this paper
• Toxoplasma gondii autophagy-related protein ATG7 maintains apicoplast inheritance by stabilizing and lipidating ATG8.

  2023cites this paper
• Autophagy induced by Cyprinid herpesvirus 3 (CyHV-3) facilitated intracellular viral replication and extracellular viral yields in common carp brain cells.

  2023cites this paper
• MAGED2 Depletion Promotes Stress-Induced Autophagy by Impairing the cAMP/PKA Pathway

  2023cites this paper
• MARCH7-mediated ubiquitination decreases the solubility of ATG14 to inhibit autophagy.

  2023cites this paper
• Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease

  2023cites this paper
• Cezanne promoted autophagy through PIK3C3 stabilization and PIK3C2A transcription in lung adenocarcinoma

  2023cites this paper
• Advances in the potential roles of Cullin-RING ligases in regulating autoimmune diseases

  2023cites this paper
• Ubiquitination Is a Novel Post-Translational Modification of VMP1 in Autophagy of Human Tumor Cells

  2023cites this paper
• Autophagy/Mitophagy Regulated by Ubiquitination: A Promising Pathway in Cancer Therapeutics

  2023cites this paper
• The role of autophagy in viral infections

  2023cites this paper
• Autophagy in the liver

  2022cites this paper
• Striatal ZBTB16 Is Associated With Cognitive Deficits in Alzheimer Disease Mice

  2022cites this paper
• CDK7/GRP78 signaling axis contributes to tumor growth and metastasis in osteosarcoma

  2022cites this paper
• Modelling the Human Blood–Brain Barrier in Huntington Disease

  2022cites this paper
• Degradation Mechanism of Autophagy-Related Proteins and Research Progress

  2022cites this paper
• Targeting the Type 5 Metabotropic Glutamate Receptor: A Potential Therapeutic Strategy for Neurodegenerative Diseases?

  2022cites this paper
• MicroRNAs Influence the Migratory Ability of Human Umbilical Vein Endothelial Cells

  2022cites this paper
• The dual roles of autophagy and the GPCRs-mediating autophagy signaling pathway after cerebral ischemic stroke

  2022cites this paper
• Regulation of autophagy—transcriptional, posttranscriptional, translational, and posttranslational mechanisms

  2022cites this paper
• Metabotropic Glutamate Receptor 2/3 Activation Improves Motor Performance and Reduces Pathology in Heterozygous zQ175 Huntington Disease Mice

  2021influential citation
• Autophagy Modulation by Viral Infections Influences Tumor Development

  2021cites this paper
• Bioinformatics Analysis of ZBTB16 as a Prognostic Marker for Ewing's Sarcoma

  2021cites this paper
• Noncanonical Metabotropic Glutamate Receptor 5 Signaling in Alzheimer's Disease.

  2021cites this paper
• Receptor–Receptor Interactions and Glial Cell Functions with a Special Focus on G Protein-Coupled Receptors

  2021cites this paper
• Cell type-specific roles of PAR1 in Coxsackievirus B3 infection

  2021cites this paper
• A Destiny for Degradation: Interplay between Cullin-RING E3 Ligases and Autophagy.

  2021cites this paper
• Optineurin deletion disrupts metabotropic glutamate receptor 5-mediated regulation of ERK1/2, GSK3β/ZBTB16, mTOR/ULK1 signaling in autophagy.

  2021cites this paper
• Class III phosphatidylinositol 3-kinase complex I subunit NRBF2/Atg38 - from cell and structural biology to health and disease

  2021cites this paper
• New Avenues for the Treatment of Huntington’s Disease

  2021cites this paper
• DAPK3 inhibits gastric cancer progression via activation of ULK1-dependent autophagy

  2020cites this paper
• Human induced pluripotent stem cell models of neurodegenerative disorders for studying the biomedical implications of autophagy.

  2020cites this paper
• Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development

  2020cites this paper
• Streptococcus pneumoniae hijacks host autophagy by deploying CbpC as a decoy for Atg14 depletion

  2020cites this paper
• mGluR5 Contribution to Neuropathology in Alzheimer Mice Is Disease Stage-Dependent.

  2020cites this paper
• Aβ oligomers induce sex-selective pathophysiological mGluR5 signaling in Alzheimer mice

  2020cites this paper
• LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13

  2020cites this paper
• The Convergence of Extracellular Vesicle and GPCR Biology.

  2020cites this paper
• The Roles of Ubiquitin in Mediating Autophagy

  2020cites this paper
• The role of ubiquitination and deubiquitination in cancer metabolism

  2020cites this paper
• Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

  2020cites this paper
• The G protein-Coupled Metabotropic Glutamate Receptor 1 controls neuronal macroautophagy

  2020cites this paper
• Aβ oligomers induce pathophysiological mGluR5 signaling in Alzheimer’s disease model mice in a sex-selective manner

  2020cites this paper
• TITLE: Aβ oligomers induce sex-selective differences in mGluR5 pharmacology and pathophysiological signaling in Alzheimer mice

  2020cites this paper
• Autophagy and Viral Infection

  2019cites this paper
• Sex-specific pathophysiological mGluR5-dependent Aβ oligomer signaling in Alzheimer mice

  2019cites this paper
• Suppression of autophagy during mitosis via CUL4-RING ubiquitin ligases-mediated WIPI2 polyubiquitination and proteasomal degradation

  2019cites this paper
• Ubiquitin-mediated regulation of autophagy

  2019cites this paper
• Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists

  2019cites this paper
• Systematic analysis of F-box proteins reveals a new branch of the yeast mating pathway

  2019cites this paper
• Autophagy is increased following either pharmacological or genetic silencing of mGluR5 signaling in Alzheimer’s disease mouse models

  2018cites this paper
• Autophagy: An Essential Degradation Program for Cellular Homeostasis and Life

  2018cites this paper
• EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis

  2018cites this paper
• Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System

  2018cites this paper
• Antiproliferative activities of the second-generation antipsychotic drug sertindole against breast cancers with a potential application for treatment of breast-to-brain metastases

  2018cites this paper
• Phosphorylation of ULK1 affects autophagosome fusion and links chaperone-mediated autophagy to macroautophagy

  2018cites this paper
• Dopamine Receptor Subtypes Differentially Regulate Autophagy

  2018cites this paper
• Functional analysis of Cullin 3 E3 ligases in tumorigenesis.

  2018influential citation
• mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux.

  2018cites this paper
• A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors

  2018cites this paper
• LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn's disease patients.

  2017cites this paper
• Gαq Signaling in the Regulation of Autophagy and Heart Failure.

  2017cites this paper
• Emerging Mechanisms in Initiating and Terminating Autophagy.

  2017cites this paper
• Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer's disease.

  2017cites this paper
• The dexamethasone induced osteogenic differentiation of dental follicle cells.

  2017cites this paper
• VPS34 Acetylation Controls Its Lipid Kinase Activity and the Initiation of Canonical and Non-canonical Autophagy.

  2017cites this paper
• Role of PLZF as a tumor suppressor in prostate cancer

  2017cites this paper
• mGluR5 antagonism increases autophagy and prevents disease progression in the zQ175 mouse model of Huntington’s disease

  2017influential citation
• PTK2-mediated degradation of ATG3 impedes cancer cells susceptible to DNA damage treatment

  2017cites this paper
• Tangshen formula attenuates diabetic renal injuries by upregulating autophagy via inhibition of PLZF expression

  2017cites this paper
• Activation of G&agr;q in Cardiomyocytes Increases Vps34 Activity and Stimulates Autophagy

  2017cites this paper
• The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion.

  2017cites this paper
• Cullin-RING ligases in regulation of autophagy

  2016cites this paper
• Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination.

  2016cites this paper
• Autophagy in leukocytes and other cells: mechanisms, subsystem organization, selectivity, and links to innate immunity

  2016cites this paper
• PtdIns(4,5)P2 signaling regulates ATG14 and autophagy

  2016cites this paper
• RNF166 Determines Recruitment of Adaptor Proteins during Antibacterial Autophagy.

  2016cites this paper
• The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34.

  2016cites this paper
• Cullin-RING ligases in regulation

  2016cites this paper
• Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth*♦

  2016cites this paper
• G protein γ subunit 7 induces autophagy and inhibits cell division

  2016cites this paper
• Regulated activation of the CUL 3 ubiquitin ligase by a calcium-dependent co-adaptor complex

  2016cites this paper
• Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system

  2015cites this paper