Institute of Biological Chemistry and Nutrition, Department of Biofunctionality and Food Safety, University of Hohenheim, Stuttgart, Germany.
Free Radic Biol Med. 2011 Jan 1;50(1):86-92. doi: 10.1016/j.freeradbiomed.2010.10.700. Epub 2010 Oct 23.
Changes in protein turnover are among the dominant metabolic changes during aging. Of special importance is the maintenance of nuclear protein homeostasis to ensure a coordinated cellular metabolism. Therefore, in the nucleus a special PARP-1-mediated mechanism of proteasomal activation exists to ensure a rapid degradation of oxidized nuclear proteins. It was already demonstrated earlier that the cytosolic proteasomal system declines dramatically with aging, whereas the nuclear proteasome remains less affected. We demonstrate here that the stress-mediated proteasomal activation in the nucleus declines during replicative senescence of human fibroblasts. Furthermore, we clearly show that this decline in the PARP-1-mediated proteasomal activation is due to a decline in the expression and activity of PARP-1 in senescent fibroblasts. In a final study we show that this process also happens in vivo, because the protein expression level of PARP-1 is significantly lower in the skin of aged donors compared to that of young ones. Therefore, we conclude that the rate-limiting factor in poly(ADP-ribose)-mediated proteasomal activation in oxidative stress is PARP-1 and not the nuclear proteasome itself.
蛋白质周转率的变化是衰老过程中主要的代谢变化之一。特别重要的是维持核蛋白稳态，以确保协调的细胞代谢。因此，在核内存在一种特殊的 PARP-1 介导的蛋白酶体激活机制，以确保氧化核蛋白的快速降解。先前已经证明，细胞质蛋白酶体系统在衰老过程中急剧下降，而核蛋白酶体受影响较小。我们在这里证明，在人成纤维细胞的复制性衰老过程中，应激介导的核蛋白酶体激活会下降。此外，我们清楚地表明，PARP-1 介导的蛋白酶体激活的这种下降是由于衰老成纤维细胞中 PARP-1 的表达和活性下降所致。在最后的研究中，我们表明这个过程也发生在体内，因为与年轻人相比，老年人皮肤中 PARP-1 的蛋白表达水平显著降低。因此，我们得出结论，聚（ADP-核糖）介导的氧化应激中蛋白酶体激活的限速因素是 PARP-1，而不是核蛋白酶体本身。
