Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2011 May 31;108(22):9119-24. doi: 10.1073/pnas.1100028108. Epub 2011 May 13.
The ubiquitin-recognition protein Ufd1 facilitates clearance of misfolded proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Here we report that prolonged ER stress represses Ufd1 expression to trigger cell cycle delay, which contributes to ERAD. Remarkably, down-regulation of Ufd1 enhances ubiquitination and destabilization of Skp2 mediated by the anaphase-promoting complex or cyclosome bound to Cdh1 (APC/C(Cdh1)), resulting in accumulation of the cyclin-dependent kinase inhibitor p27 and a concomitant cell cycle delay during the G1 phase that enables more efficient clearance of misfolded proteins. Mechanistically, nuclear Ufd1 recruits the deubiquitinating enzyme USP13 to counteract APC/C(Cdh1)-mediated ubiquitination of Skp2. Our data identify a coordinated cell cycle response to prolonged ER stress through regulation of the Cdh1-Skp2-p27 axis by Ufd1 and USP13.
泛素识别蛋白 Ufd1 通过内质网（ER）相关降解（ERAD）途径促进错误折叠蛋白的清除。在这里，我们报告说，长期的 ER 应激抑制 Ufd1 的表达，引发细胞周期延迟，这有助于 ERAD。值得注意的是，下调 Ufd1 增强了 Skp2 的泛素化和不稳定性，这是由与 Cdh1（APC/C（Cdh1））结合的后期促进复合物或细胞周期蛋白体介导的，导致细胞周期抑制剂 p27 的积累，并在 G1 期出现细胞周期延迟，从而更有效地清除错误折叠的蛋白质。在机制上，核 Ufd1 招募去泛素化酶 USP13 来抵消 APC/C（Cdh1）介导的 Skp2 的泛素化。我们的数据通过 Ufd1 和 USP13 对 Cdh1-Skp2-p27 轴的调节，确定了对长期 ER 应激的协调细胞周期反应。
