Ligand-dependent downregulation of MR1 cell surface expression.

Autor:	Salio M; MRC 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., Awad W; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia., Veerapen N; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston B15 2TT, Birmingham, United Kingdom., Gonzalez-Lopez C; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom., Kulicke C; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health & Science University, Portland, OR 97239.; Research Department, Portland Veterans Administration Healthcare System, Portland, OR 97239., Waithe D; MRC Centre for Computational Biology, The Wolfson Imaging Centre, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom., Martens AWJ; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom., Lewinsohn DM; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health & Science University, Portland, OR 97239.; Research Department, Portland Veterans Administration Healthcare System, Portland, OR 97239., Hobrath JV; Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom., Cox LR; School of Chemistry, University of Birmingham, Birmingham B15 2TT, United Kingdom., Rossjohn J; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom., Besra GS; Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston B15 2TT, Birmingham, United Kingdom; mariolina.salio@imm.ox.ac.uk g.besra@bham.ac.uk., Cerundolo V; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 May 12; Vol. 117 (19), pp. 10465-10475. Date of Electronic Publication: 2020 Apr 27.
DOI:	10.1073/pnas.2003136117
Abstrakt:	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. Competing Interests: The authors declare no competing interest. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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