Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo 1130033, Japan.
Int J Mol Sci. 2020 May 23;21(10):3683. doi: 10.3390/ijms21103683.
Protein folding is a substantively error prone process, especially when it occurs in the endoplasmic reticulum (ER). The highly exquisite machinery in the ER controls secretory protein folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol; these misfolded proteins are then degraded by the ubiquitin-proteasome system termed as the ER-associated degradation (ERAD). The 26S proteasome is a multisubunit protease complex that recognizes and degrades ubiquitinated proteins in an ATP-dependent manner. The complex structure of the 26S proteasome requires exquisite regulation at the transcription, translation, and molecular assembly levels. Nuclear factor erythroid-derived 2-related factor 1 (Nrf1; NFE2L1), an ER-resident transcription factor, has recently been shown to be responsible for the coordinated expression of all the proteasome subunit genes upon proteasome impairment in mammalian cells. In this review, we summarize the current knowledge regarding the transcriptional regulation of the proteasome, as well as recent findings concerning the regulation of Nrf1 transcription activity in ER homeostasis and metabolic processes.
蛋白质折叠是一个容易出错的过程，特别是在发生在内质网（ER）中时。内质网中高度精密的机制控制着分泌蛋白的折叠，识别异常折叠状态，并将永久性错误折叠的蛋白质从内质网反向转运回细胞质；这些错误折叠的蛋白质随后被泛素-蛋白酶体系统降解，称为内质网相关降解（ERAD）。26S 蛋白酶体是一种多亚基蛋白酶复合物，以 ATP 依赖性方式识别和降解泛素化蛋白。26S 蛋白酶体的复杂结构需要在转录、翻译和分子组装水平上进行精确的调节。核因子红细胞衍生 2 相关因子 1（Nrf1；NFE2L1），一种内质网驻留转录因子，最近已被证明负责在哺乳动物细胞的蛋白酶体受损时协调表达所有蛋白酶体亚基基因。在这篇综述中，我们总结了蛋白酶体转录调节的最新知识，以及关于 Nrf1 转录活性在内质网稳态和代谢过程中的调节的最新发现。
