Ligand-dependent downregulation of MR1 cell surface expression

Mariolina Salio, Wael Awad, Natacha Veerapen, Claudia Gonzalez-Lopez, Corinna Kulicke, Dominic Waithe, Anne W.J. Martens, David M. Lewinsohn, Judith V. Hobrath, Liam R. Cox, Jamie Rossjohn, Gurdyal S. Besra, Vincenzo Cerundolo

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Abstract

The antigen-presenting molecule MR1 presents riboflavin-based metabolites to Mucosal-Associated Invariant T (MAIT) cells. While MR1 egress to the cell surface is ligand-dependent, the ability of small-molecule ligands to impact on MR1 cellular trafficking remains unknown. Arising from an in silico screen of the MR1 ligand-binding pocket, we identify one ligand, 3-([2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]formamido)propanoic acid, DB28, as well as an analog, methyl 3-([2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]formamido)propanoate, NV18.1, that down-regulate MR1 from the cell surface and retain MR1 molecules in the endoplasmic reticulum (ER) in an immature form. DB28 and NV18.1 compete with the known MR1 ligands, 5-OP-RU and acetyl-6-FP, for MR1 binding and inhibit MR1-dependent MAIT cell activation. Crystal structures of the MAIT T cell receptor (TCR) complexed with MR1-DB28 and MR1-NV18.1, show that these two ligands reside within the A′pocket of MR1. Neither ligand forms a Schiff base with MR1 molecules; both are nevertheless sequestered by a network of hydrophobic and polar contacts. Accordingly, we define a class of compounds that inhibits MR1 cellular trafficking.

Original languageEnglish (US)
Pages (from-to)10465-10475
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number19
DOIs
StatePublished - May 12 2020

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    Salio, M., Awad, W., Veerapen, N., Gonzalez-Lopez, C., Kulicke, C., Waithe, D., Martens, A. W. J., Lewinsohn, D. M., Hobrath, J. V., Cox, L. R., Rossjohn, J., Besra, G. S., & Cerundolo, V. (2020). Ligand-dependent downregulation of MR1 cell surface expression. Proceedings of the National Academy of Sciences of the United States of America, 117(19), 10465-10475. https://doi.org/10.1073/pnas.2003136117