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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Apoptosis Regulatory Proteins / genetics
-
Apoptosis Regulatory Proteins / metabolism*
-
Beclin-1
-
Class III Phosphatidylinositol 3-Kinases / genetics
-
Class III Phosphatidylinositol 3-Kinases / metabolism
-
Endosomal Sorting Complexes Required for Transport / genetics
-
Endosomal Sorting Complexes Required for Transport / metabolism*
-
Gene Expression Regulation / physiology*
-
HeLa Cells
-
Humans
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Nedd4 Ubiquitin Protein Ligases
-
Phosphatidylinositol 3-Kinases / genetics
-
Phosphatidylinositol 3-Kinases / metabolism
-
Protein Stability
-
Proteolysis
-
Ubiquitin / chemistry
-
Ubiquitin / metabolism
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism*
-
Ubiquitination
Substances
-
Apoptosis Regulatory Proteins
-
BECN1 protein, human
-
Beclin-1
-
Endosomal Sorting Complexes Required for Transport
-
Membrane Proteins
-
Ubiquitin
-
Nedd4 Ubiquitin Protein Ligases
-
Nedd4 protein, human
-
Ubiquitin-Protein Ligases
-
Phosphatidylinositol 3-Kinases
-
Class III Phosphatidylinositol 3-Kinases