Le Ly Thi Huong Luu, Park Seoyoung, Lee Jung Hoon, Kim Yun Kyung, Lee Min Jae
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea; Inspharmtech Inc., Seoul 08511, Korea.
Mol Cells. 2024 Jan;47(1):100001. doi: 10.1016/j.mocell.2023.12.001. Epub 2023 Dec 18.
In eukaryotes, a primary protein quality control (PQC) process involves the destruction of conformationally misfolded proteins through the ubiquitin-proteasome system. Because approximately one-third of eukaryotic proteomes fold and assemble within the endoplasmic reticulum (ER) before being sent to their destinations, the ER plays a crucial role in PQC. The specific functions and biochemical roles of several E3 ubiquitin ligases involved in ER-associated degradation in mammals, on the other hand, are mainly unknown. We identified 2 E3 ligases, ubiquitin protein ligase E3 component N-recognin 1 (UBR1) and ubiquitin protein ligase E3 component N-recognin 2 (UBR2), which are the key N-recognins in the N-degron pathway and participate in the ER stress response in mammalian cells by modulating their stability. Cells lacking UBR1 and UBR2 are hypersensitive to ER stress-induced apoptosis. Under normal circumstances, these proteins are polyubiquitinated through Lys48-specific linkages and are then degraded by the 26S proteasome. In contrast, when cells are subjected to ER stress, UBR1 and UBR2 exhibit greater stability, potentially as a cellular adaptive response to stressful conditions. Although the precise mechanisms underlying these findings require further investigation, our findings show that cytoplasmic UBR1 and UBR2 have anti-ER stress activities and contribute to global PQC in mammals. These data also reveal an additional level of complexity within the mammalian ER-associated degradation system, implicating potential involvement of the N-degron pathway.
在真核生物中，一种主要的蛋白质质量控制（PQC）过程涉及通过泛素 - 蛋白酶体系统破坏构象错误折叠的蛋白质。由于大约三分之一的真核生物蛋白质组在内质网（ER）中折叠和组装后才被送往其目的地，因此内质网在PQC中起着至关重要的作用。另一方面，哺乳动物中几种参与内质网相关降解的E3泛素连接酶的具体功能和生化作用主要尚不清楚。我们鉴定出了两种E3连接酶，即泛素蛋白连接酶E3组分N - 识别蛋白1（UBR1）和泛素蛋白连接酶E3组分N - 识别蛋白2（UBR2），它们是N - 端规则途径中的关键N - 识别蛋白，并通过调节其稳定性参与哺乳动物细胞的内质网应激反应。缺乏UBR1和UBR2的细胞对内质网应激诱导的凋亡高度敏感。在正常情况下，这些蛋白质通过赖氨酸48特异性连接被多泛素化，然后被26S蛋白酶体降解。相反，当细胞受到内质网应激时，UBR1和UBR2表现出更高的稳定性，这可能是细胞对压力条件的一种适应性反应。尽管这些发现背后的确切机制需要进一步研究，但我们的研究结果表明，细胞质中的UBR1和UBR2具有抗内质网应激活性，并有助于哺乳动物的整体PQC。这些数据还揭示了哺乳动物内质网相关降解系统内的另一个复杂层面，暗示了N - 端规则途径的潜在参与。
