Ligand-dependent downregulation of MR1 cell surface expression.
Antigen Presentation
Cell Line
Cell Membrane
/ metabolism
Down-Regulation
Gene Expression Regulation
/ genetics
Histocompatibility Antigens Class I
/ metabolism
Humans
Ligands
Lymphocyte Activation
Minor Histocompatibility Antigens
/ metabolism
Mucosal-Associated Invariant T Cells
/ metabolism
Protein Transport
Receptors, Antigen, T-Cell, alpha-beta
/ metabolism
Riboflavin
/ metabolism
THP-1 Cells
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
12 05 2020
12 05 2020
Historique:
pubmed:
29
4
2020
medline:
22
8
2020
entrez:
29
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32341160
pii: 2003136117
doi: 10.1073/pnas.2003136117
pmc: PMC7229755
doi:
Substances chimiques
Histocompatibility Antigens Class I
0
Ligands
0
MR1 protein, human
0
Minor Histocompatibility Antigens
0
Receptors, Antigen, T-Cell, alpha-beta
0
Riboflavin
TLM2976OFR
Banques de données
PDB
['6PVC', '6PVD']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
10465-10475Subventions
Organisme : Medical Research Council
ID : MR/S005382/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C399/A2291
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 11331
Pays : United Kingdom
Organisme : BLRD VA
ID : I01 BX000533
Pays : United States
Organisme : Wellcome Trust
ID : 081569/Z/06/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S000542/1
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI134790
Pays : United States
Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
Références
Immunol Lett. 2017 Mar;183:1-7
pubmed: 28119072
Microbes Infect. 2005 Mar;7(3):552-9
pubmed: 15777741
J Biol Chem. 2005 Jun 3;280(22):21183-93
pubmed: 15802267
J Exp Med. 2013 Oct 21;210(11):2305-20
pubmed: 24101382
Nat Immunol. 2017 Apr;18(4):402-411
pubmed: 28166217
Nat Commun. 2013;4:2142
pubmed: 23846752
Cell Rep. 2019 Sep 17;28(12):3061-3076.e5
pubmed: 31533031
PLoS Biol. 2010 Jun 29;8(6):e1000407
pubmed: 20613858
Cell Rep. 2019 Sep 17;28(12):3077-3091.e5
pubmed: 31533032
J Exp Med. 2014 Jul 28;211(8):1601-10
pubmed: 25049333
Nature. 2014 May 15;509(7500):361-5
pubmed: 24695216
Nat Immunol. 2016 May;17(5):531-7
pubmed: 27043408
J Immunol. 2013 Nov 15;191(10):5268-77
pubmed: 24108697
Curr Opin Immunol. 2016 Jun;40:123-9
pubmed: 27115617
Nat Immunol. 2010 Aug;11(8):701-8
pubmed: 20581831
Immunol Cell Biol. 2018 Jul;96(6):607-617
pubmed: 29451704
Curr Opin Immunol. 2017 Jun;46:66-74
pubmed: 28494326
J Leukoc Biol. 2018 Sep;104(3):473-486
pubmed: 29668066
Immunity. 2016 Jan 19;44(1):32-45
pubmed: 26795251
Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):E4753-61
pubmed: 24248359
J Immunol. 2017 Oct 15;199(8):2631-2638
pubmed: 28877992
Immunol Cell Biol. 2018 Jul;96(6):588-597
pubmed: 29393543
Nat Immunol. 2017 Dec;18(12):1321-1331
pubmed: 28991267
J Immunol. 2003 Jun 15;170(12):6090-8
pubmed: 12794138
PLoS Pathog. 2013;9(10):e1003681
pubmed: 24130485
Curr Opin Immunol. 2015 Jun;34:28-34
pubmed: 25603223
J Immunol. 2016 Aug 1;197(3):971-82
pubmed: 27307560
Elife. 2017 May 18;6:
pubmed: 28518056
Nat Immunol. 2020 Apr;21(4):400-411
pubmed: 32123373
J Leukoc Biol. 2017 Nov;102(5):1261-1269
pubmed: 28807929
Nat Rev Immunol. 2019 Oct;19(10):643-657
pubmed: 31308521
J Exp Med. 2014 Jul 28;211(8):1585-600
pubmed: 25049336
Nature. 2012 Nov 29;491(7426):717-23
pubmed: 23051753
J Exp Med. 2015 Jun 29;212(7):1095-108
pubmed: 26101265
J Clin Invest. 2015 Apr;125(4):1752-62
pubmed: 25751065
Nat Commun. 2018 Jan 17;9(1):253
pubmed: 29343684
Sci Rep. 2019 Mar 18;9(1):4797
pubmed: 30886396
Front Immunol. 2015 Jul 28;6:388
pubmed: 26284072
Nat Immunol. 2019 Sep;20(9):1110-1128
pubmed: 31406380
Curr Opin Immunol. 2007 Jun;19(3):354-64
pubmed: 17428648
Curr Opin Immunol. 2016 Jun;40:43-50
pubmed: 27065088
J Immunol. 1998 Oct 15;161(8):4066-77
pubmed: 9780177
J Exp Med. 1999 Jul 5;190(1):31-41
pubmed: 10429668
Clin Exp Immunol. 2014 May;176(2):266-74
pubmed: 24450998
J Immunol. 2011 Apr 15;186(8):4744-50
pubmed: 21402896
Cell Rep. 2019 Sep 17;28(12):3249-3262.e5
pubmed: 31533045
Blood. 2011 Jan 27;117(4):1250-9
pubmed: 21084709