title: Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1.
abstract: Beclin 1, a subunit of the class III phosphatidylinositol 3-kinase complex, is a tumour suppressor with a central role in endocytic trafficking, cytokinesis and the cross-regulation between autophagy and apoptosis. Interestingly, not only reduced expression but also overexpression of Beclin 1 is correlated with cancer development and metastasis. Thus it seems necessary for the cell to balance the protein levels of Beclin 1. In the present study we describe a regulatory link between Beclin 1 and the ubiquitin ligase Nedd4 (neural-precursor-cell-expressed developmentally down-regulated 4). We establish Nedd4 as a novel binding partner of Beclin 1 and demonstrate that Nedd4 polyubiquitinates Beclin 1 with Lys11- and Lys63-linked chains. Importantly, Nedd4 expression controls the stability of Beclin 1, and depletion of the Beclin 1-interacting protein VPS34 causes Nedd4-mediated proteasomal degradation of Beclin 1 via Lys11-linked polyubiquitin chains. Beclin 1 is thus the first tumour suppressor reported to be controlled by Lys11-linked polyubiquitination.
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, 0310 Oslo, Norway.
authors.forename: Harald W
authors.initials: HW
authors.lastname: Platta
authors.forename: Hilde
authors.initials: H
authors.lastname: Abrahamsen
authors.forename: Sigrid B
authors.initials: SB
authors.lastname: Thoresen
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000071186:Beclin-1; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D025801:Ubiquitin; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D058546:Class III Phosphatidylinositol 3-Kinases