Caspase cleavage of BimEL triggers a positive feedback amplification of apoptotic signaling.
Members of the Bcl-2 protein family that share only the Bcl-2 homology 3 (BH3) domain are known mostly as sentinels for apoptotic stimuli and initiators of apoptosis. One BH3-only protein, Bim, is the major physiological antagonist of the prosurvival proteins in B and T lymphocytes. It is required for hematopoietic homeostasis and to preclude autoimmunity. Here, we show that the Bim(EL) isoform, which was predominant in T cells, existed in both phosphorylated and unphosphorylated forms. Whereas the unphosphorylated Bim(EL) was sequestered to microtubules by means of a direct interaction with tubulin, the phosphorylated protein was released from microtubules. The freed Bim(EL) was subjected to caspase cleavage at an early stage of apoptosis induced by stimuli that activate either the mitochondria- or death receptor-dependent apoptosis pathway. The N-terminally cleaved Bim(EL) became hyperactive in inducing apoptosis because of its more efficient targeting of Bcl-2. Thus, unlike many other BH3-only proteins, Bim(EL) can be activated downstream of the caspase cascade, leading to a positive feedback amplification of apoptotic signals.
Chen
Dan
D
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3202, USA.
Zhou
Qiang
Q
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000502:physiology*; D005246:Feedback; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins; D008870:Microtubules / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D014404:Tubulin / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; D020169:Caspases