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.
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http://dx.doi.org/10.1073/pnas.2003136117 | DOI Listing |
Am J Med Genet A
December 2024
Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
You-Hoover-Fong syndrome (YHFS) is a rare autosomal recessive disorder characterized by global developmental delay, microcephaly, dysmorphic facial features, and a spectrum of neurodevelopmental abnormalities. YHFS is caused by pathogenic variants in TELO2, a gene involved in regulation of the cell cycle. To date, 29 individuals with YHFS have been reported and none of them has been reported to develop tumors.
View Article and Find Full Text PDFImmunity
December 2024
Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland. Electronic address:
The major histocompatibility complex (MHC) class I-related molecule MHC-class-I-related protein 1 (MR1) presents metabolites to distinct MR1-restricted T cell subsets, including mucosal-associated invariant T (MAIT) and MR1T cells. However, self-reactive MR1T cells and the nature of recognized antigens remain underexplored. Here, we report a cell endogenous carbonyl adduct of adenine (8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.
View Article and Find Full Text PDFFront Immunol
December 2024
State Key Laboratory of Biocontrol/School of Marine Sciences, Sun Yat-sen University, Guangzhou, China.
Introduction: Hypoxia stress renders aquatic animals more susceptible to bacterial disease, yet the underlying mechanism remains elusive.
Methods: We conducted an acute hypoxia stress experiment to investigate the impact of stress on the immune response of via transcriptome analysis, RT-qPCR and Western blot.
Results: Our results showed that acute hypoxia stress disrupted the tissue architecture, and significantly changed the gene expression profiles in the hepatopancreas of shrimp.
J Environ Manage
December 2024
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, China. Electronic address:
Environ Res
December 2024
School of Environmental Science and Engineering, Guilin University of Technology, Guilin, 541000, China; State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing, 100012, China. Electronic address:
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