Autoadaptive ER-Associated Degradation Defines a Preemptive Unfolded Protein Response Pathway (Retracted Article)
Autoadaptive ER-Associated Degradation Defines a Preemptive Unfolded Protein Response Pathway (Retracted Article)
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DOI：
10.1016/j.molcel.2013.10.016
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发表时间：
2013-12-26
期刊：
影响因子：
16
通讯作者：
Molinari, Maurizio
中科院分区：
文献类型：
--
作者：
Bernasconi, Riccardo;Galli, Carmela;Molinari, Maurizio
折叠缺陷蛋白必须从内质网 (ER) 中有效清除，以防止折叠环境的扰动并维持细胞蛋白质稳态。错误折叠的蛋白质参与围绕 E3 泛素连接酶构建的错位机制（dislocons），促进其跨内质网膜的运输、多泛素化和蛋白酶体降解。在这里，我们报告了 HRD1 脱位子的内在不稳定性和支架蛋白 HERP 的组成型、快速周转。我们表明，HRD1 脱位子完整性依赖于 HRD1 客户端的存在，HRD1 客户端以剂量依赖性方式中断控制 HERP 更新的 UBC6e/RNF5/p97/蛋白酶体控制的中继。我们建议 ER 相关降解 (ERAD) 部署自适应调节途径（统称为 ERAD 调节），以快速调整降解活性以适应错误折叠的蛋白质负载，并抢占未折叠蛋白质反应 (U PR) 的激活。
Folding-defective proteins must be cleared efficiently from the endoplasmic reticulum (ER) to prevent perturbation of the folding environment and to maintain cellular proteostasis. Misfolded proteins engage dislocation machineries (dislocons) built around E3 ubiquitin ligases that promote their transport across the ER membrane, their polyubiquitylation, and their proteasomal degradation. Here, we report on the intrinsic instability of the HRD1 dislocon and the constitutive, rapid turnover of the scaffold protein HERP. We show that HRD1 dislocon integrity relies on the presence of HRD1 clients that interrupt, in a dose-dependent manner, the UBC6e/RNF5/p97/proteasome-controlled relay that controls HERP turnover. We propose that ER-associated degradation (ERAD) deploys autoadaptive regulatory pathways, collectively defined as ERAD tuning, to rapidly adapt degradation activity to misfolded protein load and to preempt the unfolded protein response (U PR) activation.