The translocon-associated protein (TRAP) complex regulates quality control of N-linked glycosylation during ER stress.
The translocon-associated protein (TRAP) complex regulates quality control of N-linked glycosylation during ER stress.
复制标题
DOI：
10.1126/sciadv.abc6364
复制
发表时间：
2021-01
期刊：
影响因子：
13.6
通讯作者：
Contessa JN
中科院分区：
文献类型：
--
作者：
Phoomak C;Cui W;Hayman TJ;Yu SH;Zhao P;Wells L;Steet R;Contessa JN
一种检测 N-糖基化的新方法揭示了 TRAP 复合物的作用和细胞状态特异性调节的机制。天冬酰胺 (N) 连接的糖基化是内质网 (ER) 稳态所必需的，但在内质网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，我们引入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，敲除SSR3或SSR4亚基的细胞会随着时间的推移恢复N-糖基化，同时内质网应激转录特征减弱。 ER 应激的激活或 ER 伴侣 BiP 的沉默分别加剧或挽救糖基化缺陷，表明 SSR3 和 SSR4 在 ER 应激期间启用 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 复合物在应激条件下调节 ER 糖蛋白质量控制。
A new method for detecting N-glycosylation reveals a role for the TRAP complex and a mechanism for cell state–specific regulation. 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.
登录
查看更多内容
影响因子：
14.8
作者：
Lopez-Sambrooks C;Shrimal S;Khodier C;Flaherty DP;Rinis N;Charest JC;Gao N;Zhao P;Wells L;Lewis TA;Lehrman MA;Gilmore R;Golden JE;Contessa JN
通讯作者：
Contessa JN
影响因子：
14.8
作者：
Hebert, Daniel N.;Lamriben, Lydia;Powers, Evan T.;Kelly, Jeffery W.
通讯作者：
Kelly, Jeffery W.
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
DOI：
10.1158/1078-0432.ccr-09-3331
发表时间：
2010-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Contessa JN;Bhojani MS;Freeze HH;Ross BD;Rehemtulla A;Lawrence TS
通讯作者：
Lawrence TS
影响因子：
21.3
作者：
通讯作者：
--