Microbiology & Immunology - Theses

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Author: Cruz Gomez, Sebastian Matias × End date: 2023 × Start date: 2020 × Subject: Immunology ×

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    Identification and characterization of proteins and mechanisms involved in the uptake and traffic of vitamin B related antigens
    Cruz Gomez, Sebastian Matias ( 2021)
    Major histocompatibility complex, class I-related (MR1) presents Vitamin B-related antigens (VitBAg) at the cell surface to activate mucosal associated invariant T (MAIT) cells, directing homeostasis and immune responses. Although previous work has suggested endocytosis as a participant in MR1 presentation, how these antigens are captured by the cell is currently unknown. It is likely that MR1 ligands are uptake as metabolites for they have several structural similarities with molecules known to be transported through solute carrier (SLC) transporters. Here, we shown that flavins are pathway-specific inhibitors of MR1-5-OP-RU, and do not inhibit MR1-Ac-6-FP upregulation. We revealed that 5-OP-RU, ribityl lumazine (RL) and bacterial VitBAg, but not folate derived ligands, enter the cell through SLC52A family of riboflavin transporters, as their expression increases MR1 presentation and MAIT cell activation in a riboflavin modulated manner. In contrast, knock-outs models SLC52A family drastically reduce the incorporation of RLs but do not abolish the capacity to present 5-OP-RU through MR1. In fact, pathway specific inhibitors of MR1-5-OP-RU and MR1-Ac-6-FP extend to nucleosides, nucleobases and other drugs, arguing for the contribution of more SLC transporters in their uptake. Likewise, MR1 presentation during infection is increased by ligand-producing bacteria located in the cytosol, stating a cytosolic step to reach empty MR1 molecules. Finally, we showed that 5-OP-RU alters the metabolome of cells like LPS, leading to changes in their transcriptome profile. Our results unveil a new route for 5-OP-RU, RL and bacterial VitBAg uptake through SLC52A transporters, contributing to their capture and modulating MR1 presentation, together with a new potential role of 5-OP-RU as a pathogen-associated molecular patterns (PAMPs) molecule.