Tomalin Lewis Elwood, Day Alison Michelle, Underwood Zoe Elizabeth, Smith Graham Robert, Dalle Pezze Piero, Rallis Charalampos, Patel Waseema, Dickinson Bryan Craig, Bähler Jürg, Brewer Thomas Francis, Chang Christopher Joh-Leung, Shanley Daryl Pierson, Veal Elizabeth Ann
Institute for Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Bioinformatics Support Unit, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Free Radic Biol Med. 2016 Jun;95:333-48. doi: 10.1016/j.freeradbiomed.2016.02.035. Epub 2016 Mar 2.
Reactive oxygen species, such as H2O2, can damage cells but also promote fundamental processes, including growth, differentiation and migration. The mechanisms allowing cells to differentially respond to toxic or signaling H2O2 levels are poorly defined. Here we reveal that increasing external H2O2 produces a bi-phasic response in intracellular H2O2. Peroxiredoxins (Prx) are abundant peroxidases which protect against genome instability, ageing and cancer. We have developed a dynamic model simulating in vivo changes in Prx oxidation. Remarkably, we show that the thioredoxin peroxidase activity of Prx does not provide any significant protection against external rises in H2O2. Instead, our model and experimental data are consistent with low levels of extracellular H2O2 being efficiently buffered by other thioredoxin-dependent activities, including H2O2-reactive cysteines in the thiol-proteome. We show that when extracellular H2O2 levels overwhelm this buffering capacity, the consequent rise in intracellular H2O2 triggers hyperoxidation of Prx to thioredoxin-resistant, peroxidase-inactive form/s. Accordingly, Prx hyperoxidation signals that H2O2 defenses are breached, diverting thioredoxin to repair damage.
活性氧物质，如过氧化氢（H₂O₂），既能损伤细胞，也能促进包括生长、分化和迁移在内的基本过程。细胞对有毒或作为信号分子的H₂O₂水平产生差异反应的机制尚不清楚。在此，我们揭示，增加细胞外H₂O₂会在细胞内H₂O₂中产生双相反应。过氧化物酶体增殖物激活受体（Prx）是丰富的过氧化物酶，可防止基因组不稳定、衰老和癌症。我们开发了一个动态模型来模拟Prx氧化的体内变化。值得注意的是，我们发现Prx的硫氧还蛋白过氧化物酶活性并不能为抵抗细胞外H₂O₂的升高提供任何显著的保护作用。相反，我们的模型和实验数据表明，细胞外低水平的H₂O₂可被其他硫氧还蛋白依赖性活性有效缓冲，包括硫醇蛋白质组中具有H₂O₂反应性的半胱氨酸。我们表明，当细胞外H₂O₂水平超过这种缓冲能力时，细胞内H₂O₂随之升高会触发Prx过度氧化为对硫氧还蛋白具有抗性的、过氧化物酶失活的形式。因此，Prx过度氧化表明H₂O₂防御被突破，从而使硫氧还蛋白转向修复损伤。
