Endoplasmic reticulum chaperones stabilize ligand-receptive MR1 molecules for efficient presentation of metabolite antigens

McWilliam, Hamish E. G., Mak, Jeffrey Y. W., Awad, Wael, Zorkau, Matthew, Cruz-Gomez, Sebastian, Lim, Hui Jing, Yan, Yuting, Wormald, Sam, Dagley, Laura F., Eckle, Sidonia B. G., Corbett, Alexandra J., Liu, Haiyin, Li, Shihan, Reddiex, Scott J. J., Mintern, Justine D., Liu, Ligong, McCluskey, James, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Fairlie, David P. and Villadangos, Jose A. 2020. Endoplasmic reticulum chaperones stabilize ligand-receptive MR1 molecules for efficient presentation of metabolite antigens. Proceedings of the National Academy of Sciences 117 (40) , pp. 24974-24985. 10.1073/pnas.2011260117

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of Acceptance:	21 August 2020
Last Modified:	09 Nov 2022 09:32
URI:	https://orca.cardiff.ac.uk/id/eprint/136035

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