The antigen-presenting molecule MR1 binds host-generated riboflavin catabolites.

Abdelaal, Mohamed R., Deng, Jieru, McInerney, Mitchell P., Ito, Emi, Purcell, Anthony W., Yamasaki, Sho, Villadangos, Jose A., McWilliam, Hamish E. G., Gherardin, Nicholas A., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and Awad, Wael 2025. The antigen-presenting molecule MR1 binds host-generated riboflavin catabolites. Journal of Experimental Medicine 223 (2) , e20250711. 10.1084/jem.20250711

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Abstract

MHC class I-related protein (MR1) presents vitamin B-based antigens (Ags) to mucosal-associated invariant T (MAIT) cells. While microbial riboflavin (RF) precursors are well-documented MR1 ligands, it is unclear whether host-generated RF catabolites influence MR1 immunity. Here, we report that RF catabolites, including 10-formylmethylflavin (FMF), lumichrome, lumiflavin, and alloxazine, bind to MR1 with moderate affinity, while RF itself binds weakly. In contrast to the MR1-upregulating microbial RF precursors, RF catabolites reduced the surface level of MR1 by inducing its retention in the endoplasmic reticulum and inhibiting exit. These RF catabolites weakly competed with vitamin B-based Ags for MR1 binding, thereby selectively inhibiting MAIT activation. The crystal structures of MR1 with RF, FMF, lumiflavin, and lumichrome show binding in the A'-pocket of MR1. Here, lumichrome formed a "flavin bond" covalent interaction with MR1-Lys43 differing from the typical Schiff base. Collectively, we identified three-ringed isoalloxazines that bind MR1 and reduce surface levels, suggesting a potential role in dampening MAIT cell immunity.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: Title: cc by, Type: cc by
Publisher:	Rockefeller University Press
ISSN:	0022-1007
Date of First Compliant Deposit:	9 December 2025
Date of Acceptance:	22 October 2025
Last Modified:	09 Dec 2025 12:45
URI:	https://orca.cardiff.ac.uk/id/eprint/183047

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