作为哺乳动物ER应激中心传感器的N-识别蛋白UBR1和UBR2

IF 3.7 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecules and Cells Pub Date : 2024-01-01 DOI:10.1016/j.mocell.2023.12.001
Ly Thi Huong Luu Le , Seoyoung Park , Jung Hoon Lee , Yun Kyung Kim , Min Jae Lee
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引用次数: 0

摘要

在真核生物中,主要的蛋白质质量控制(PQC)过程包括通过泛素-蛋白酶体系统破坏构象错误的蛋白质。由于真核生物蛋白质组约有三分之一在内质网(ER)中折叠和组装,然后被送往目的地,因此内质网在 PQC 中起着至关重要的作用。另一方面,哺乳动物中参与ER相关降解的几种E3泛素连接酶的具体功能和生化作用主要尚不清楚。我们发现了两种E3连接酶--泛素蛋白连接酶E3元件N-识别素1(UBR1)和泛素蛋白连接酶E3元件N-识别素2(UBR2),它们是N-降解途径中的关键N-识别素,通过调节其稳定性参与哺乳动物细胞的ER应激反应。缺乏 UBR1 和 UBR2 的细胞对 ER 应激诱导的细胞凋亡不敏感。在正常情况下,这些蛋白质通过 Lys48 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ER胁迫时,UBR1和UBR2表现出更高的稳定性,这可能是细胞对胁迫条件的一种适应性反应。尽管这些发现的确切机制还需要进一步研究,但我们的研究结果表明,细胞质中的 UBR1 和 UBR2 具有抗 ER 应激活性,有助于哺乳动物体内的全局 PQC。这些数据还揭示了哺乳动物ER相关降解系统的另一个复杂层次,暗示了N-降解子途径的潜在参与。
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N-recognins UBR1 and UBR2 as central ER stress sensors in mammals

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.

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来源期刊
Molecules and Cells
Molecules and Cells 生物-生化与分子生物学
CiteScore
6.60
自引率
10.50%
发文量
83
审稿时长
2.3 months
期刊介绍: Molecules and Cells is an international on-line open-access journal devoted to the advancement and dissemination of fundamental knowledge in molecular and cellular biology. It was launched in 1990 and ISO abbreviation is ''Mol. Cells''. Reports on a broad range of topics of general interest to molecular and cell biologists are published. It is published on the last day of each month by the Korean Society for Molecular and Cellular Biology.
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