title: Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria.
abstract: 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, TDVD(133) and DQLD(149), 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.
authors.affiliation: VIB, Department for Molecular Biomedical Research, Ghent, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Wirawan
authors.forename: L
authors.initials: L
authors.lastname: Vande Walle
authors.forename: K
authors.initials: K
authors.lastname: Kersse
authors.forename: S
authors.initials: S
authors.lastname: Cornelis
authors.forename: S
authors.initials: S
authors.lastname: Claerhout
authors.forename: I
authors.initials: I
authors.lastname: Vanoverberghe
authors.forename: R
authors.initials: R
authors.lastname: Roelandt
authors.forename: R
authors.initials: R
authors.lastname: De Rycke
authors.forename: J
authors.initials: J
authors.lastname: Verspurten
authors.forename: W
authors.initials: W
authors.lastname: Declercq
authors.forename: P
authors.initials: P
authors.lastname: Agostinis
authors.forename: T
authors.initials: T
authors.lastname: Vanden Berghe
authors.forename: S
authors.initials: S
authors.lastname: Lippens
authors.forename: P
authors.initials: P
authors.lastname: Vandenabeele
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D007377:Interleukin-3; D008565:Membrane Proteins; D011994:Recombinant Proteins; D019869:Phosphatidylinositol 3-Kinases; D020169:Caspases