Legewie Stefan, Blüthgen Nils, Herzel Hanspeter
Institute for Theoretical Biology, Humboldt University, Berlin, Germany.
PLoS Comput Biol. 2006 Sep 15;2(9):e120. doi: 10.1371/journal.pcbi.0020120. Epub 2006 Jul 28.
The intrinsic, or mitochondrial, pathway of caspase activation is essential for apoptosis induction by various stimuli including cytotoxic stress. It depends on the cellular context, whether cytochrome c released from mitochondria induces caspase activation gradually or in an all-or-none fashion, and whether caspase activation irreversibly commits cells to apoptosis. By analyzing a quantitative kinetic model, we show that inhibition of caspase-3 (Casp3) and Casp9 by inhibitors of apoptosis (IAPs) results in an implicit positive feedback, since cleaved Casp3 augments its own activation by sequestering IAPs away from Casp9. We demonstrate that this positive feedback brings about bistability (i.e., all-or-none behaviour), and that it cooperates with Casp3-mediated feedback cleavage of Casp9 to generate irreversibility in caspase activation. Our calculations also unravel how cell-specific protein expression brings about the observed qualitative differences in caspase activation (gradual versus all-or-none and reversible versus irreversible). Finally, known regulators of the pathway are shown to efficiently shift the apoptotic threshold stimulus, suggesting that the bistable caspase cascade computes multiple inputs into an all-or-none caspase output. As cellular inhibitory proteins (e.g., IAPs) frequently inhibit consecutive intermediates in cellular signaling cascades (e.g., Casp3 and Casp9), the feedback mechanism described in this paper is likely to be a widespread principle on how cells achieve ultrasensitivity, bistability, and irreversibility.
半胱天冬酶激活的内在途径，即线粒体途径，对于包括细胞毒性应激在内的各种刺激诱导细胞凋亡至关重要。这取决于细胞环境，即从线粒体释放的细胞色素c是以逐渐的方式还是以全或无的方式诱导半胱天冬酶激活，以及半胱天冬酶激活是否使细胞不可逆转地走向凋亡。通过分析一个定量动力学模型，我们发现凋亡抑制蛋白（IAPs）对半胱天冬酶-3（Casp3）和Casp9的抑制会导致一种隐含的正反馈，因为裂解的Casp3通过将IAPs从Casp9上隔离来增强其自身的激活。我们证明这种正反馈会导致双稳态（即全或无行为），并且它与Casp3介导的Casp9反馈裂解协同作用，以在半胱天冬酶激活中产生不可逆性。我们的计算还揭示了细胞特异性蛋白表达如何导致在半胱天冬酶激活中观察到的定性差异（逐渐与全或无以及可逆与不可逆）。最后，已知的该途径调节因子被证明能有效地改变凋亡阈值刺激，这表明双稳态半胱天冬酶级联将多个输入计算为一个全或无的半胱天冬酶输出。由于细胞抑制蛋白（如IAPs）经常抑制细胞信号级联中的连续中间体（如Casp3和Casp9），本文描述的反馈机制可能是细胞实现超敏感性、双稳态和不可逆性的一个广泛原则。
