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The Tumour Suppressor TMEM127 Is a Nedd4-Family E3 Ligase Adaptor Required by Salmonella SteD to Ubiquitinate and Degrade MHC Class II Molecules.
Cell Host & Microbe ( IF 20.6 ) Pub Date : 2020-06-10 , DOI: 10.1016/j.chom.2020.04.024
Eric Alix 1 , Camilla Godlee 1 , Ondrej Cerny 1 , Samkeliso Blundell 1 , Romina Tocci 1 , Sophie Matthews 1 , Mei Liu 1 , Jonathan N Pruneda 2 , Kirby N Swatek 3 , David Komander 4 , Tabitha Sleap 1 , David W Holden 1
Affiliation  

The Salmonella enterica effector SteD depletes mature MHC class II (mMHCII) molecules from the surface of infected antigen-presenting cells through ubiquitination of the cytoplasmic tail of the mMHCII β chain. Here, through a genome-wide mutant screen of human antigen-presenting cells, we show that the NEDD4 family HECT E3 ubiquitin ligase WWP2 and a tumor-suppressing transmembrane protein of unknown biochemical function, TMEM127, are required for SteD-dependent ubiquitination of mMHCII. Although evidently not involved in normal regulation of mMHCII, TMEM127 was essential for SteD to suppress both mMHCII antigen presentation in mouse dendritic cells and MHCII-dependent CD4+ T cell activation. We found that TMEM127 contains a canonical PPxY motif, which was required for binding to WWP2. SteD bound to TMEM127 and enabled TMEM127 to interact with and induce ubiquitination of mature MHCII. Furthermore, SteD also underwent TMEM127- and WWP2-dependent ubiquitination, which both contributed to its degradation and augmented its activity on mMHCII.



中文翻译:


肿瘤抑制因子 TMEM127 是沙门氏菌 SteD 所需的 Nedd4 系列 E3 连接酶适配器,用于泛素化和降解 MHC II 类分子。



肠道沙门氏菌效应子 SteD 通过泛素化 mMHCII β 链的细胞质尾部,从受感染的抗原呈递细胞表面耗尽成熟的 MHC II 类 (mMHCII) 分子。在这里,通过对人类抗原呈递细胞的全基因组突变筛选,我们发现NEDD4家族HECT E3泛素连接酶WWP2和生化功能未知的肿瘤抑制跨膜蛋白TMEM127是mMHCII的SteD依赖性泛素化所必需的。尽管显然不参与 mMHCII 的正常调节,但 TMEM127 对于 SteD 抑制小鼠树突状细胞中 mMHCII 抗原呈递和 MHCII 依赖性 CD4 + T 细胞激活至关重要。我们发现 TMEM127 包含一个典型的 PPxY 基序,这是与 WWP2 结合所必需的。 SteD 与 TMEM127 结合,使 TMEM127 能够与成熟 MHCII 相互作用并诱导成熟 MHCII 泛素化。此外,SteD 还经历了 TMEM127 和 WWP2 依赖性泛素化,这既促进了其降解,又增强了其对 mMHCII 的活性。

更新日期:2020-07-08
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