The execution phase of apoptosis is a critical process in programmed cell death in response to a multitude of cellular stresses. A crucial component of this pathway is the apoptosome, a platform for the activation of pro-caspase 9 (PC9). Recent findings have shown that autocleavage of PC9 to Caspase 9 (C9) p35/p12 not only permits XIAP-mediated C9 inhibition but also temporally shuts down apoptosome activity, forming a molecular timer. In order to delineate the combined contributions of XIAP and the apoptosome molecular timer to apoptosis execution we utilised a systems modelling approach. We demonstrate that cooperative recruitment of PC9 to the apoptosome, based on existing PC9-apoptosome interaction data, is important for efficient formation of PC9 homodimers, autocatalytic cleavage and dual regulation by XIAP and the molecular timer across biologically relevant PC9 and APAF1 concentrations. Screening physiologically relevant concentration ranges of apoptotic proteins, we discovered that the molecular timer can prevent apoptosis execution in specific scenarios after complete or partial mitochondrial outer membrane permeabilisation (MOMP). Furthermore, its ability to prevent apoptosis is intricately tied to a synergistic combination with XIAP. Finally, we demonstrate that simulations of these processes are prognostic of survival in stage III colorectal cancer and that the molecular timer may promote apoptosis resistance in a subset of patients. Based on our findings, we postulate that the physiological function of the molecular timer is to aid XIAP in the shutdown of caspase-mediated apoptosis execution. This shutdown potentially facilitates switching to pro-inflammatory caspase-independent responses subsequent to Bax/Bak pore formation.

中文翻译：

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凋亡小体分子计时器与 XIAP 协同抑制凋亡执行并有助于预测结直肠癌的存活率。

细胞凋亡的执行阶段是响应多种细胞应激的程序性细胞死亡的关键过程。该途径的一个重要组成部分是凋亡体，它是激活半胱天冬酶原 9 (PC9) 的平台。最近的研究结果表明，PC9 自动裂解为 Caspase 9 (C9) p35/p12 不仅允许 XIAP 介导的 C9 抑制，而且还会暂时关闭凋亡体活性，形成分子计时器。为了描绘 XIAP 和凋亡分子计时器对细胞凋亡执行的综合贡献，我们使用了系统建模方法。我们证明，基于现有的 PC9-凋亡体相互作用数据，将 PC9 协同募集到凋亡体对于 PC9 同源二聚体的有效形成很重要，XIAP 的自催化裂解和双重调节以及生物相关 PC9 和 APAF1 浓度的分子计时器。筛选凋亡蛋白的生理相关浓度范围，我们发现分子计时器可以在完全或部分线粒体外膜透化 (MOMP) 后阻止特定情况下的凋亡执行。此外，其防止细胞凋亡的能力与与 XIAP 的协同组合密切相关。最后，我们证明这些过程的模拟可以预测 III 期结直肠癌的存活率，并且分子计时器可能会促进一部分患者的细胞凋亡抵抗。根据我们的发现，我们假设分子计时器的生理功能是帮助 XIAP 关闭半胱天冬酶介导的细胞凋亡执行。