Caspase cleavage of Bim<inf>EL</inf> triggers a positive feedback amplification of apoptotic signaling

Abstract

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 BimEL 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 BimEL 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 BimEL became hyperactive in inducing apoptosis because of its more efficient targeting of Bcl-2. Thus, unlike many other BH3-only proteins, BimEL can be activated downstream of the caspase cascade, leading to a positive feedback amplification of apoptotic signals.