XIAP As a Positive Feedback Regulator of Capase Activation

Abstract

STKE Inhibitor of apoptosis proteins (IAPs) are best known for their roles as inhibitors of caspases and thus of apoptotic cell death. Legewie et al. develop a mathematical model of the core intrinsic apoptotic process involving Apaf-1, caspase 9, caspase 3, and X-linked IAP (XIAP). In the wild-type model, as active Apaf-1 concentration increased, the time course with which active caspase 3 was produced decreased as expected. When the activation of caspase 3 was plotted against the concentration of active Apaf-1, a bistable and irreversible state was observed both in the wild-type model and in a caspase 9 mutant model. This suggested that the positive feedback between caspase 9 and caspase 3 was not the only contributor to bistability in the system. Further analysis suggested that XIAP contributed a positive feedback to caspase 3 activation. Caspase 3 was proposed to sequester XIAP away from caspase 9 under conditions of strong stimulation, thereby allowing caspase 9 to become further activated and ultimately allowing caspase 3 to be activated. The bistability and irreversibility of the models depended on the concentrations of both caspase 3 and caspase 9, with only the wild-type model showing irreversibility in the physiological concentrations of each caspase, indicating that both caspase 3-mediated feedback and XIAP-mediated feedback contribute to irreversible bistability under physiological conditions. The models echo observed differences in cellular responses to apoptotic stimuli by showing that the all-or-none threshold of the system is influenced by the abundance of caspase 3, caspase 9, and XIAP. — NRG PLoS Comput. Biol. 2 , e120 (2006).