Strang Laboratory of Apoptosis and Cancer Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA.
Cell. 2013 Apr 25;153(3):614-27. doi: 10.1016/j.cell.2013.03.040.
Protein degradation by the ubiquitin-proteasome system is central to cell homeostasis and survival. Defects in this process are associated with diseases such as cancer and neurodegenerative disorders. The 26S proteasome is a large protease complex that degrades ubiquitinated proteins. Here, we show that ADP-ribosylation promotes 26S proteasome activity in both Drosophila and human cells. We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome α subunits to relieve 20S repression by PI31. Additionally, PI31 modification increases binding to and sequestration of dp27 and dS5b from 19S regulatory particles, promoting 26S assembly. Inhibition of TNKS by either RNAi or a small-molecule inhibitor, XAV939, blocks this process to reduce 26S assembly. These results unravel a mechanism of proteasome regulation that can be targeted with existing small-molecule inhibitors.
蛋白质的泛素-蛋白酶体系统降解对细胞内稳态和存活至关重要。该过程的缺陷与癌症和神经退行性疾病等疾病有关。26S 蛋白酶体是一种大型的蛋白酶复合物，可降解泛素化的蛋白质。在这里，我们证明了 ADP-核糖基化可促进果蝇和人类细胞中的 26S 蛋白酶体活性。我们确定了 ADP-核糖基转移酶 tankyrase（TNKS）和 19S 组装伴侣 dp27 和 dS5b 是蛋白酶体调节剂 PI31 的直接结合伙伴。TNKS 介导的 PI31 的 ADP-核糖基化极大地降低了其与 20S 蛋白酶体 α 亚基的亲和力，从而减轻了 PI31 对 20S 的抑制作用。此外，PI31 的修饰增加了与 dp27 和 dS5b 从 19S 调节颗粒的结合和隔离，从而促进了 26S 的组装。用 RNAi 或小分子抑制剂 XAV939 抑制 TNKS 会阻止这一过程，从而减少 26S 的组装。这些结果揭示了一种可以用现有的小分子抑制剂靶向的蛋白酶体调节机制。
