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Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling
eLife ( IF 6.4 ) Pub Date : 2020-07-02 , DOI: 10.7554/elife.57306
Emma J Fenech 1 , Federica Lari 1 , Philip D Charles 2 , Roman Fischer 2 , Marie Laétitia-Thézénas 2 , Katrin Bagola 1 , Adrienne W Paton 3 , James C Paton 3 , Mads Gyrd-Hansen 1 , Benedikt M Kessler 2, 4 , John C Christianson 1, 5, 6
Affiliation  

Ubiquitin ligases (E3s) embedded in the endoplasmic reticulum (ER) membrane regulate essential cellular activities including protein quality control, calcium flux, and sterol homeostasis. At least 25 different, transmembrane domain (TMD)-containing E3s are predicted to be ER-localised, but for most their organisation and cellular roles remain poorly defined. Using a comparative proteomic workflow, we mapped over 450 protein-protein interactions for 21 stably expressed, full-length E3s. Bioinformatic analysis linked ER-E3s and their interactors to multiple homeostatic, regulatory, and metabolic pathways. Among these were four membrane-embedded interactors of RNF26, a polytopic E3 whose abundance is auto-regulated by ubiquitin-proteasome dependent degradation. RNF26 co-assembles with TMEM43, ENDOD1, TMEM33 and TMED1 to form a complex capable of modulating innate immune signalling through the cGAS-STING pathway. This RNF26 complex represents a new modulatory axis of STING and innate immune signalling at the ER membrane. Collectively, these data reveal the broad scope of regulation and differential functionalities mediated by ER-E3s for both membrane-tethered and cytoplasmic processes.

中文翻译:


内质网泛素连接酶的相互作用图谱鉴定了先天免疫信号的调节剂



嵌入内质网 (ER) 膜中的泛素连接酶 (E3) 调节重要的细胞活动,包括蛋白质质量控​​制、钙流动和甾醇稳态。预计至少有 25 个不同的、含有跨膜结构域 (TMD) 的 E3 位于内质网,但对于大多数来说,它们的组织和细胞作用仍然不明确。使用比较蛋白质组学工作流程,我们绘制了 21 个稳定表达的全长 E3 的 450 多个蛋白质-蛋白质相互作用。生物信息学分析将 ER-E3 及其相互作用因子与多种稳态、调节和代谢途径联系起来。其中有四个膜嵌入的 RNF26 相互作用子,RNF26 是一种多胞体 E3,其丰度通过泛素蛋白酶体依赖性降解自动调节。 RNF26 与 TMEM43、ENDOD1、TMEM33 和 TMED1 共同组装,形成能够通过 cGAS-STING 途径调节先天免疫信号传导的复合物。这种 RNF26 复合物代表了 STING 和 ER 膜先天免疫信号传导的新调节轴。总的来说,这些数据揭示了 ER-E3 介导的膜束缚过程和细胞质过程的广泛调节和差异功能。
更新日期:2020-07-02
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