4.7 Article

Evidence that CED-9/Bcl2 and CED-4/Apaf-1 localization is not consistent with the current model for C. elegans apoptosis induction

Journal

CELL DEATH AND DIFFERENTIATION
Volume 19, Issue 3, Pages 406-415

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.104

Keywords

CED-4; Apaf-1; CED-9; Bcl-2; C. elegans; apoptosis

Funding

  1. CR-UK CDA [C11852/A4500]
  2. Wellcome Trust [0909444/Z/09/Z, 081923/Z/07/Z]
  3. CRUK [C11852/A8052]
  4. Cancer Research UK [14695] Funding Source: researchfish
  5. Wellcome Trust [081923/Z/07/Z] Funding Source: Wellcome Trust

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In C. elegans, the BH3-only domain protein EGL-1, the Apaf-1 homolog CED-4 and the CED-3 caspase are required for apoptosis induction, whereas the Bcl-2 homolog CED-9 prevents apoptosis. Mammalian B-cell lymphoma 2 (Bcl-2) inhibits apoptosis by preventing the release of the Apaf-1 (apoptotic protease-activating factor 1) activator cytochrome c from mitochondria. In contrast, C. elegans CED-9 is thought to inhibit CED-4 by sequestering it at the outer mitochondrial membrane by direct binding. We show that CED-9 associates with the outer mitochondrial membrane within distinct foci that do not overlap with CED-4, which is predominantly perinuclear and does not localize to mitochondria. CED-4 further accumulates in the perinuclear space in response to proapoptotic stimuli such as ionizing radiation. This increased accumulation depends on EGL-1 and is abrogated in ced-9 gain-of-function mutants. CED-4 accumulation is not sufficient to trigger apoptosis execution, even though it may prime cells for apoptosis. Our results suggest that the cell death protection conferred by CED-9 cannot be solely explained by a direct interaction with CED-4. Cell Death and Differentiation (2012) 19, 406-415; doi: 10.1038/cdd.2011.104; published online 2 September 2011

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