Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Commun. 2024 Oct 29;15(1):9344. doi: 10.1038/s41467-024-53755-8.
Caspases regulate and execute a spectrum of functions including cell deaths, non-apoptotic developmental functions, and stress responses. Despite these disparate roles, the same core cell-death machinery is required to enzymatically activate caspase proteolytic activities. Thus, it remains enigmatic how distinct caspase functions are differentially regulated. In this study, we show that Xeroderma pigmentosum protein XPD has a conserved function in activating the expression of stress-responsive caspases in C. elegans and human cells without triggering cell death. Using C. elegans, we show XPD-1-dependent activation of CED-3 caspase promotes survival upon genotoxic UV irradiation and inversely suppresses responses to non-genotoxic insults such as ER and osmotic stressors. Unlike the TFDP ortholog DPL-1 which is required for developmental apoptosis in C. elegans, XPD-1 only activates stress-responsive functions of caspase. This tradeoff balancing responses to genotoxic and non-genotoxic stress may explain the seemingly contradictory nature of caspase-mediated stress resilience versus sensitivity under different stressors.
半胱天冬酶调节和执行一系列功能，包括细胞死亡、非凋亡性发育功能和应激反应。尽管这些功能各不相同，但需要相同的核心细胞死亡机制来酶促激活半胱天冬酶的蛋白水解活性。因此，不同的半胱天冬酶功能如何被差异调节仍然是一个谜。在这项研究中，我们表明 Xeroderma pigmentosum 蛋白 XPD 在激活秀丽隐杆线虫和人类细胞中应激反应性半胱天冬酶的表达方面具有保守功能，而不会引发细胞死亡。我们使用秀丽隐杆线虫表明，CED-3 半胱天冬酶依赖于 XPD-1 的激活促进了在致基因突变的 UV 照射下的存活，并且相反地抑制了对非致基因突变的应激的反应，如内质网和渗透应激源。与线虫中凋亡所必需的 TFDP 同源物 DPL-1 不同，XPD-1 仅激活应激反应性半胱天冬酶的功能。这种对致基因突变和非致基因突变应激的反应的权衡可能解释了在不同应激源下，半胱天冬酶介导的应激弹性与敏感性之间看似矛盾的性质。
