英国MRC分子生物学实验室Ramanujan S. Hegde研究小组发现监测蛋白酶体组装过程中失败的质量控制因子。2021年8月27日，国际知名学术期刊《科学》发表了这一成果。

研究人员发现过量的PSMC5，一个蛋白酶体基的亚单位，在哺乳动物细胞中被HERC1泛素连接酶靶向降解。HERC1通过其同源的装配伴侣PAAF1识别未装配的PSMC5。由于PAAF1只在组装后解离，HERC1也可以参与后期的组装中间物，如PSMC4-PSMC5-PAAF1复合物。导致小鼠神经变性的HERC1错义突变体在识别和泛素化PSMC5-PAAF1复合物方面有障碍。因此，蛋白酶体组装因子可以作为泛素连接酶的适配器，用于促进消除未组装的中间物并维持蛋白质的平衡。

据介绍，在真核细胞中，一半的蛋白质在多蛋白复合体中作为亚单位发挥作用。亚单位的合成不平衡导致未组装的中间物，这些中间物必须被降解来减少细胞毒性。

附：英文原文

Title: Identification of a quality-control factor that monitors failures during proteasome assembly

Author: Eszter Zavodszky, Sew-Yeu Peak-Chew, Szymon Juszkiewicz, Ana J. Narvaez, Ramanujan S. Hegde

Issue&Volume: 2021/08/27

Abstract: In eukaryotic cells, half of all proteins function as subunits within multiprotein complexes. Imbalanced synthesis of subunits leads to unassembled intermediates that must be degraded to minimize cellular toxicity. Here, we found that excess PSMC5, a subunit of the proteasome base, was targeted for degradation by the HERC1 ubiquitin ligase in mammalian cells. HERC1 identified unassembled PSMC5 by its cognate assembly chaperone PAAF1. Because PAAF1 only dissociates after assembly, HERC1 could also engage later assembly intermediates such as the PSMC4-PSMC5-PAAF1 complex. A missense mutant of HERC1 that causes neurodegeneration in mice was impaired in the recognition and ubiquitination of the PSMC5-PAAF1 complex. Thus, proteasome assembly factors can serve as adaptors for ubiquitin ligases to facilitate elimination of unassembled intermediates and maintain protein homeostasis.

DOI: 10.1126/science.abc6500

Source: https://science.sciencemag.org/content/373/6558/998