1. The Tumour Suppressor TMEM127 Is a Nedd4-Family E3 Ligase Adaptor Required by Salmonella SteD to Ubiquitinate and Degrade MHC Class II Molecules.
- Author
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Alix E, Godlee C, Cerny O, Blundell S, Tocci R, Matthews S, Liu M, Pruneda JN, Swatek KN, Komander D, Sleap T, and Holden DW
- Subjects
- Animals, Antigen Presentation, CRISPR-Cas Systems, Cell Line, Dendritic Cells immunology, Dendritic Cells microbiology, Female, Host-Pathogen Interactions, Humans, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mutation, Protein Binding, Salmonella Infections immunology, Salmonella Infections microbiology, T-Lymphocytopenia, Idiopathic CD4-Positive immunology, T-Lymphocytopenia, Idiopathic CD4-Positive microbiology, Virulence, Bacterial Proteins physiology, Histocompatibility Antigens Class II metabolism, Membrane Proteins physiology, Salmonella typhimurium physiology, Ubiquitin-Protein Ligases physiology, Ubiquitination
- Abstract
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., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Imperial College London. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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