Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control
Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control
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DOI：
10.1073/pnas.1100028108
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发表时间：
2011-05-31
影响因子：
11.1
通讯作者：
Ronai, Ze'ev A.
中科院分区：
文献类型：
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作者：
Chen, Meifan;Gutierrez, Gustavo J.;Ronai, Ze'ev A.
泛素识别蛋白Ufd 1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Ufd 1的表达，触发细胞周期延迟，这有助于ERAD。值得注意的是，Ufd 1的下调增强了由与Cdh 1结合的后期促进复合物或环体（APC/C（Cdh 1））介导的Skp 2的泛素化和去稳定化，导致细胞周期蛋白依赖性激酶抑制剂p27的积累和伴随的G1期细胞周期延迟，从而能够更有效地清除错误折叠的蛋白质。从机制上讲，核Ufd 1招募去泛素化酶USP 13来抵消APC/C（Cdh 1）介导的Skp 2泛素化。我们的数据确定了一个协调的细胞周期响应延长ER压力通过调节Cdh 1-Skp 2-p27轴Ufd 1和USP 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.