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The antigen presenting molecule MR1 binds 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, Victoria 3800, Australia.

Biorxiv : the Preprint Server for Biology
|August 12, 2025
PubMed

Insights

Host-generated riboflavin catabolites bind to the MR1 protein, reducing its cell surface expression and dampening Mucosal-Associated Invariant T (MAIT) cell immunity. This suggests a new mechanism for immune regulation.

Area of Science:

  • Immunology
  • Structural Biology
  • Biochemistry

Background:

  • Major histocompatibility-complex (MHC) class I-related (MR1) protein presents vitamin B-derived antigens to Mucosal-Associated Invariant T (MAIT) cells.
  • While microbial riboflavin precursors are known MR1 ligands, the role of host-generated riboflavin catabolites in MR1-mediated immunity is unclear.

Purpose of the Study:

  • To investigate the binding of host-generated riboflavin catabolites to MR1.
  • To determine the effect of these catabolites on MR1 cell surface expression and MAIT cell activation.
  • To elucidate the structural basis of MR1-ligand interactions.

Main Methods:

  • Ligand binding assays to assess affinity of riboflavin catabolites for MR1.
  • Cell surface expression analysis of MR1.
  • MAIT cell activation assays.
  • X-ray crystallography to determine the structure of MR1-ligand complexes.

Main Results:

  • Riboflavin catabolites (FMF, lumichrome, lumiflavin, alloxazine) bind MR1 with moderate affinity, while riboflavin binds weakly.
  • These catabolites reduce MR1 cell surface expression by retaining MR1 in the endoplasmic reticulum (ER).
  • Crystal structures reveal binding in the A eal-pocket, with lumichrome forming a covalent bond with MR1-Lys43.
  • Catabolites weakly compete with vitamin B antigens, inhibiting MAIT cell activation.

Conclusions:

  • Host-generated three-ring isoalloxazines can bind MR1 and downregulate its cell surface expression.
  • This interaction potentially dampens MAIT cell immunity.
  • Identified a novel mechanism of immune regulation involving MR1 and endogenous metabolites.
Keywords:
MAIT cellsMR1antigen presentationflavin bondlumichromeriboflavin

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