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The translocon-associated protein (TRAP) complex regulates quality control of N-linked glycosylation during ER stress
Science Advances ( IF 13.6 ) Pub Date : 2021-01-15 , DOI: 10.1126/sciadv.abc6364
Chatchai Phoomak 1 , Wei Cui 1 , Thomas J Hayman 1 , Seok-Ho Yu 2 , Peng Zhao 3 , Lance Wells 3 , Richard Steet 2 , Joseph N Contessa 1, 4
Affiliation  

Asparagine (N)–linked glycosylation is required for endoplasmic reticulum (ER) homeostasis, but how this co- and posttranslational modification is maintained during ER stress is unknown. Here, we introduce a fluorescence-based strategy to detect aberrant N-glycosylation in individual cells and identify a regulatory role for the heterotetrameric translocon-associated protein (TRAP) complex. Unexpectedly, cells with knockout of SSR3 or SSR4 subunits restore N-glycosylation over time concurrent with a diminished ER stress transcriptional signature. Activation of ER stress or silencing of the ER chaperone BiP exacerbates or rescues the glycosylation defects, respectively, indicating that SSR3 and SSR4 enable N-glycosylation during ER stress. Protein levels of the SSR3 subunit are ER stress and UBE2J1 dependent, revealing a mechanism that coordinates upstream N-glycosylation proficiency with downstream ER-associated degradation and proteostasis. The fidelity of N-glycosylation is not static in both nontransformed and tumor cells, and the TRAP complex regulates ER glycoprotein quality control under conditions of stress.



中文翻译:

易位子相关蛋白 (TRAP) 复合物调节内质网应激期间 N-连接糖基化的质量控制

内质网 (ER) 稳态需要天冬酰胺 (N) 连接的糖基化,但在 ER 应激期间如何维持这种共翻译和翻译后修饰尚不清楚。在这里,我们介绍了一种基于荧光的策略来检测单个细胞中的异常 N-糖基化,并确定异四聚体易位子相关蛋白 (TRAP) 复合物的调节作用。出乎意料的是,随着时间的推移,敲除 SSR3 或 SSR4 亚基的细胞恢复了 N-糖基化,同时 ER 应激转录特征减少。ER 应激的激活或 ER 伴侣 BiP 的沉默分别加剧或挽救了糖基化缺陷,表明 SSR3 和 SSR4 能够在 ER 应激期间实现 N-糖基化。SSR3 亚基的蛋白质水平依赖于 ER 应激和 UBE2J1,揭示了一种协调上游 N-糖基化能力与下游 ER 相关降解和蛋白质稳态的机制。N-糖基化的保真度在非转化细胞和肿瘤细胞中都不是静态的,TRAP 复合物在压力条件下调节 ER 糖蛋白的质量控制。

更新日期:2021-01-15
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