Endoplasmic reticulum chaperones stabilize ligand-receptive MR1 molecules for efficient presentation of metabolite antigens
- McWilliam, HEG; Mak, JYW; Awad, W; Zorkau, M; Cruz-Gomez, S; Lim, HJ; Yan, Y; Wormald, S; Dagley, LF; Eckle, SBG; Corbett, AJ; Liu, H; Li, S; Reddiex, SJJ; Mintern, JD; Liu, L; McCluskey, J; Rossjohn, J; Fairlie, DP; Villadangos, JA;
Publication Year 2020-10-06, Volume 117, Issue #40, Page 24974-24985
- Journal Title
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type
- Journal Article
- The antigen-presenting molecule MR1 (MHC class I-related protein 1) presents metabolite antigens derived from microbial vitamin B2 synthesis to activate mucosal-associated invariant T (MAIT) cells. Key aspects of this evolutionarily conserved pathway remain uncharacterized, including where MR1 acquires ligands and what accessory proteins assist ligand binding. We answer these questions by using a fluorophore-labeled stable MR1 antigen analog, a conformation-specific MR1 mAb, proteomic analysis, and a genome-wide CRISPR/Cas9 library screen. We show that the endoplasmic reticulum (ER) contains a pool of two unliganded MR1 conformers stabilized via interactions with chaperones tapasin and tapasin-related protein. This pool is the primary source of MR1 molecules for the presentation of exogenous metabolite antigens to MAIT cells. Deletion of these chaperones reduces the ER-resident MR1 pool and hampers antigen presentation and MAIT cell activation. The MR1 antigen-presentation pathway thus co-opts ER chaperones to fulfill its unique ability to present exogenous metabolite antigens captured within the ER.
- WEHI Research Division(s)
- Advanced Technology And Biology
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-11-02 04:55:17Last Modified: 2020-11-03 09:22:41