Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1.
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Platta HW, Abrahamsen H, Thoresen SB, Stenmark H
Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1.
Biochem J. 2012 Jan 1;441(1):399-406. doi: 10.1042/BJ20111424.
- PubMed ID
- 21936852 [ View in PubMed]
- 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.