Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria

By Ellen Wirawan, L. Walle, K. Kersse, S. Cornelis, S. Claerhout, Isabel Vanoverberghe, R. Roelandt, R. Rycke, Jelle Verspurten, W. Declercq and 4 more. Cell Death and Disease, 2010

711 citations recorded by the source corpus.

Autophagy and apoptosis are two important and interconnected stress-response mechanisms. However, the molecular interplay between these two pathways is not fully understood. To study the fate and function of autophagic proteins at the onset of apoptosis, we used a cellular model system in which autophagy precedes apoptosis. IL-3 depletion of Ba/F3 cells caused caspase (casp)-mediated cleavage of Beclin-1 and PI3KC3, two crucial components of the autophagy-inducing complex. We identified two casp cleavage sites in Beclin-1, TDVD133 and DQLD149, cleavage at which yields fragments lacking the autophagy-inducing capacity. Noteworthy, the C-terminal fragment, Beclin-1-C, localized predominantly at the mitochondria and sensitized the cells to apoptosis. Moreover, on isolated mitochondria, recombinant Beclin-1-C was able to induce the release of proapoptotic factors. These findings point to a mechanism by which casp-dependent generation of Beclin-1-C creates an amplifying loop enhancing apoptosis upon growth factor withdrawal.

Subfields: Epidemiology, General Health Professions, Plant Science

View Paper: https://www.semanticscholar.org/paper/09519284b8941742aa155e42b2cbd2299d3d6fd0

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In Plant Science

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Citations in the corpus

• Autophagy and the integrated stress response (2010, positive): “The C-terminal fragment of Beclin 1 that results from this cleavage acquires a new function and can amplify mitochondrion-mediated apoptosis (Wirawan et al., 2010).”
• Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis (2015, background): “Beclin 1 and class III PI3K, two components of the autophagy-inducing complex, are direct substrates of caspases [105].”