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The antigen-presenting molecule MR1 binds host-generated riboflavin catabolites
Mohamed R Abdelaal1, Jieru Deng2, Mitchell P McInerney1
1Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
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.
Insights
Host-generated riboflavin catabolites bind to MR1, reducing its surface levels and inhibiting MAIT cell activation. This suggests a role for these compounds in dampening mucosal-associated invariant T cell immunity.
Area of Science:
- Immunology
- Structural Biology
Background:
- Mucosal-associated invariant T (MAIT) cells are crucial immune sentinels.
- MHC class I-related protein (MR1) presents vitamin B-based antigens to MAIT cells.
- Microbial riboflavin precursors are known MR1 ligands, but host-derived catabolites' roles are unclear.
Purpose of the Study:
- To investigate the binding of host-generated riboflavin catabolites to MR1.
- To determine the impact of these catabolites on MR1 surface levels and MAIT cell activation.
- To elucidate the structural basis of MR1-catabolite interactions.
Main Methods:
- Surface plasmon resonance (SPR) for binding affinity.
- Flow cytometry for MR1 surface levels.
- Crystallography for structural analysis of MR1-ligand complexes.
- MAIT cell activation assays.
Main Results:
- Riboflavin catabolites (FMF, lumichrome, lumiflavin, alloxazine) bind MR1 moderately; riboflavin binds weakly.
- Catabolites reduce MR1 surface expression by ER retention, unlike RF precursors.
- Catabolites weakly compete with antigens, selectively inhibiting MAIT activation.
- Crystal structures reveal binding in the MR1 A eal-pocket; lumichrome forms a unique covalent bond with MR1-Lys43.
Conclusions:
- Host-derived three-ringed isoalloxazines bind MR1 and reduce its surface levels.
- These catabolites can dampen MAIT cell immunity by inhibiting MR1 presentation.
- Structural insights reveal novel MR1-ligand interactions, including a unique covalent bond.
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