Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1

作者：Platta Harald W; Abrahamsen Hilde; Thoresen Sigrid B; Stenmark Harald^*

来源：Biochemical Journal, 2012, 441(1): 399-406.

DOI：10.1042/BJ20111424

• cancer
• homologous with E6-associated protein C-terminus (HECT)
• neural-precursor-cell-expressed developmentally down-regulated 4 (Nedd4)
• phosphoinositide
• ubiquitination
• VPS34

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 Lys(11)- and Lys(63)-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 Lys(11)-linked polyubiquitin chains. Beclin 1 is thus the first tumour suppressor reported to be controlled by Lys(11)-linked polyubiquitination.

• 出版日期2012-1-1