Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1.
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.
Mesh Terms:
Apoptosis Regulatory Proteins, Class III Phosphatidylinositol 3-Kinases, Endosomal Sorting Complexes Required for Transport, Gene Expression Regulation, HeLa Cells, Humans, Membrane Proteins, Phosphatidylinositol 3-Kinases, Protein Stability, Proteolysis, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Apoptosis Regulatory Proteins, Class III Phosphatidylinositol 3-Kinases, Endosomal Sorting Complexes Required for Transport, Gene Expression Regulation, HeLa Cells, Humans, Membrane Proteins, Phosphatidylinositol 3-Kinases, Protein Stability, Proteolysis, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Biochem. J.
Date: Jan. 01, 2012
PubMed ID: 21936852
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