Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
Nat Commun. 2015 Apr 2;6:6609. doi: 10.1038/ncomms7609.
The Parkinson's-associated protein, DJ-1, is a highly conserved homodimer, ubiquitously expressed in cells. Here we demonstrate that DJ-1 is a 20S proteasome regulator. We show that DJ-1 physically binds the 20S proteasome and inhibits its activity, rescuing partially unfolded proteins from degradation. Consequently, DJ-1 stabilizes the cellular levels of 20S proteasome substrates, as we show for α-synuclein and p53. Furthermore, we demonstrate that following oxidative stress, DJ-1 is involved in the Nrf2-dependent oxidative stress response that leads to the upregulation of both the 20S proteasome and its regulator, NQO1. Overall, our results suggest a regulatory circuit in which DJ-1, under conditions of oxidative stress, both upregulates and inhibits the 20S proteasome, providing a rigorous control mechanism at a time when the 20S proteasome becomes the major proteolytic machinery. Such a tight regulation of the 20S proteasome may sustain the balance between the need to rapidly eliminate oxidatively damaged proteins and maintain the abundance of native, intrinsically unstructured proteins, which coordinate regulatory and signalling events.
帕金森病相关蛋白 DJ-1 是一种高度保守的同二聚体，在细胞中广泛表达。本文中我们证明 DJ-1 是 20S 蛋白酶体的调节因子。我们发现 DJ-1 可与 20S 蛋白酶体直接结合并抑制其活性，从而阻止部分变性蛋白的降解。因此，DJ-1 稳定了 20S 蛋白酶体底物在细胞中的水平，如我们在α-突触核蛋白和 p53 中所展示的。此外，我们还证实，在氧化应激后，DJ-1 参与了 Nrf2 依赖性的氧化应激反应，从而上调 20S 蛋白酶体及其调控因子 NQO1。总之，我们的结果表明，在氧化应激条件下，DJ-1 可以上调和抑制 20S 蛋白酶体，形成一个调控回路，为 20S 蛋白酶体成为主要的蛋白水解机制时提供了严格的控制机制。这种对 20S 蛋白酶体的严格调控可能维持了快速消除氧化损伤蛋白与维持固有无序蛋白丰度之间的平衡，而固有无序蛋白协调着调控和信号事件。
