title: FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation.
abstract: Vacuolar protein-sorting 34 (Vps34), the catalytic subunit in the class III PtdIns3 (phosphatidylinositol 3) kinase complexes, mediates the production of PtdIns3P, a key intracellular lipid involved in regulating autophagy and receptor degradation. However, the signal transduction pathways by which extracellular signals regulate Vps34 complexes and the downstream cellular mechanisms are not well understood. Here we show that DNA damage-activated mitotic arrest and CDK activation lead to the phosphorylation of Vps34, which provides a signal to promote its ubiquitination and proteasomal degradation mediated by FBXL20 (an F-box protein) and the associated Skp1 (S-phase kinase-associated protein-1)-Cullin1 complex, leading to inhibition of autophagy and receptor endocytosis. Furthermore, we show that the expression of FBXL20 is regulated by p53-dependent transcription. Our study provides a molecular pathway by which DNA damage regulates Vps34 complexes and its downstream mechanisms, including autophagy and receptor endocytosis, through SCF (Skp1-Cul1-F-box)-mediated ubiquitination and degradation. Since the expression of FBXL20 is regulated by p53-dependent transcription, the control of Vps34 ubiquitination and proteasomal degradation by FBXL20 and the associated SCF complex expression provides a novel checkpoint for p53 to regulate autophagy and receptor degradation in DNA damage response.
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;
authors.forename: Juan
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, 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 200032, China;
authors.forename: Daichao
authors.initials: D
authors.lastname: Xu
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;
authors.forename: Huibing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;
authors.forename: Yu
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;
authors.forename: Taijie
authors.initials: T
authors.lastname: Jin
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Jin
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;
authors.forename: Kejia
authors.initials: K
authors.lastname: Wu
authors.affiliation: Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA jyuan@hms.harvard.edu.
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D001343:Autophagy / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D045744:Cell Line, Tumor; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D004705:Endocytosis / Q000502:physiology; D044783:F-Box Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C579745:FBXL20 protein, human; D044786:S-Phase Kinase-Associated Proteins; C097351:SKP1 protein, human; D016159:Tumor Suppressor Protein p53; D058546:Class III Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex
keywords: Vps34; autophagy; p53