Conversion of Bcl-2 to a Bax-like Death Effector by Caspases

TLDR

Caspases are cysteine proteases that drive the biochemical and morphological changes of apoptosis. The loop domain of Bcl‑2 is cleaved at Asp34 by caspase‑3 in vitro, in cells overexpressing caspase‑3, and following Fas‑induced apoptosis or interleukin‑3 withdrawal. Cleavage of Bcl‑2 at Asp34 produces a death‑effector fragment that triggers cell death, accelerates Sindbis‑virus–induced apoptosis, and, by activating downstream caspases, amplifies the caspase cascade, while cleavage‑resistant mutants confer protection, indicating that caspase‑mediated Bcl‑2 cleavage guarantees cell‑death inevitability.

Abstract

Caspases are a family of cysteine proteases implicated in the biochemical and morphological changes that occur during apoptosis (programmed cell death). The loop domain of Bcl-2 is cleaved at Asp 34 by caspase-3 (CPP32) in vitro, in cells overexpressing caspase-3, and after induction of apoptosis by Fas ligation and interleukin-3 withdrawal. The carboxyl-terminal Bcl-2 cleavage product triggered cell death and accelerated Sindbis virus–induced apoptosis, which was dependent on the BH3 homology and transmembrane domains of Bcl-2. Inhibitor studies indicated that cleavage of Bcl-2 may further activate downstream caspases and contribute to amplification of the caspase cascade. Cleavage-resistant mutants of Bcl-2 had increased protection from interleukin-3 withdrawal and Sindbis virus–induced apoptosis. Thus, cleavage of Bcl-2 by caspases may ensure the inevitability of cell death.