Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, The University of Southern California, Los Angeles, CA 90089-0191, USA.
Arch Biochem Biophys. 2012 Jul 15;523(2):181-90. doi: 10.1016/j.abb.2012.04.018. Epub 2012 Apr 30.
The response and functions of proteasome regulators Pa28αβ (or 11S), Pa28γ and Pa200 in oxidative-stress adaptation (also called hormesis) was studied in murine embryonic fibroblasts (MEFs), using a well-characterized model of cellular adaptation to low concentrations (1.0-10.0 μM) of hydrogen peroxide (H(2)O(2)), which alter gene expression profiles, increasing resistance to higher levels of oxidative-stress. Pa28αβ bound to 20S proteasomes immediately upon H(2)O(2)-treatment, whereas 26S proteasomes were disassembled at the same time. Over the next 24h, the levels of Pa28αβ, Pa28γ and Pa200 proteasome regulators increased during H(2)O(2)-adaptation, whereas the 19S regulator was unchanged. Purified Pa28αβ, and to a lesser extent Pa28γ, significantly increased the ability of purified 20S proteasome to selectively degrade oxidized proteins; Pa28αβ also increased the capacity of purified immunoproteasome to selectively degrade oxidized proteins but Pa28γ did not. Pa200 regulator actually decreased 20S proteasome and immunoproteasome's ability to degrade oxidized proteins but Pa200 and poly-ADP ribose polymerase may cooperate in enabling initiation of DNA repair. Our results indicate that cytoplasmic Pa28αβ and nuclear Pa28γ may both be important regulators of proteasome's ability to degrade oxidatively-damaged proteins, and induced-expression of both 20S proteasome and immunoproteasome, and their Pa28αβ and Pa28γ regulators are important for oxidative-stress adaptation.
细胞对低浓度（1.0-10.0 μM）过氧化氢（H2O2）适应的研究表明，蛋白酶体调节剂 Pa28αβ（或 11S）、Pa28γ 和 Pa200 在氧化应激适应（也称为应激反应）中的反应和功能。该研究使用了一种经过充分验证的细胞适应低浓度过氧化氢模型，这种模型改变了基因表达谱，提高了对更高水平氧化应激的抵抗力。Pa28αβ 在 H2O2 处理后立即与 20S 蛋白酶体结合，而 26S 蛋白酶体同时被解体。在接下来的 24 小时内，Pa28αβ、Pa28γ 和 Pa200 蛋白酶体调节剂在 H2O2 适应过程中的水平增加，而 19S 调节剂则不变。纯化的 Pa28αβ，在较小程度上还有 Pa28γ，显著增加了纯化 20S 蛋白酶体选择性降解氧化蛋白的能力；Pa28αβ 还增加了纯化免疫蛋白酶体选择性降解氧化蛋白的能力，但 Pa28γ 没有。Pa200 调节剂实际上降低了 20S 蛋白酶体和免疫蛋白酶体降解氧化蛋白的能力，但 Pa200 和多聚 ADP 核糖聚合酶可能在启动 DNA 修复方面合作。我们的结果表明，细胞质 Pa28αβ 和核内 Pa28γ 可能都是蛋白酶体降解氧化损伤蛋白能力的重要调节剂，20S 蛋白酶体和免疫蛋白酶体及其 Pa28αβ 和 Pa28γ 调节剂的诱导表达对氧化应激适应很重要。
