Ligand-dependent downregulation of MR1 cell surface expression
Mariolina Salio1, Wael Awad2,3, Natacha Veerapen4
1MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom; mariolina.salio@imm.ox.ac.uk g.besra@bham.ac.uk.
Summary
New small molecules, DB28 and NV18.1, were identified that disrupt the trafficking of the MR1 antigen-presenting molecule. These compounds inhibit MR1’s cell surface presentation and MAIT cell activation.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- The Major Histocompatibility Complex class I-related molecule MR1 presents metabolites to Mucosal-Associated Invariant T (MAIT) cells.
- MR1's surface expression is ligand-dependent, but how small molecules affect its trafficking is unknown.
Purpose of the Study:
- To investigate the impact of small-molecule ligands on MR1 cellular trafficking and MAIT cell activation.
- To identify novel compounds that modulate MR1 function.
Main Methods:
- In silico screening of the MR1 ligand-binding pocket.
- Biochemical assays to assess MR1 binding and competition with known ligands.
- Crystal structure determination of MR1-ligand complexes.
- Analysis of MAIT cell activation.
Main Results:
- DB28 and NV18.1 were identified as MR1 ligands that down-regulate MR1 surface expression by retaining it in the endoplasmic reticulum.
- These ligands compete with known MR1 ligands (5-OP-RU, acetyl-6-FP) and inhibit MR1-dependent MAIT cell activation.
- Crystal structures reveal DB28 and NV18.1 bind to the MR1 A'-pocket via hydrophobic and polar interactions, without forming a Schiff base.
Conclusions:
- DB28 and NV18.1 represent a novel class of compounds that inhibit MR1 cellular trafficking.
- These findings provide new tools for studying MR1 biology and potential therapeutic strategies targeting MAIT cells.
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