Opposing roles for SNAP23 and SNAP25 in mediating MR1 trafficking and antigen presentation.

MHC class I-related protein 1 (MR1) is a highly conserved antigen presenting molecule that presents small molecule metabolites derived from diverse microbial pathogens to mucosal-associated invariant T (MAIT) cells. We have shown previously that MR1 traffics through endosomal compartments via soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, including Syntaxin 4 and vesicle-associated membrane protein (VAMP) 4. Here, we investigate the role of synaptosome-associated proteins (SNAPs), which pair with Syntaxins and VAMPs to form functional SNARE complexes, in MR1-mediated antigen presentation. Among SNAP homologs, we identify that SNAP23 contributes to the presentation of Mycobacterium tuberculosis (Mtb)-derived antigens and loss of SNAP23 reduces the number of MR1-containing vesicles during infection. In contrast, SNAP25 suppresses MR1 presentation for both intracellular pathogens Mtb and Mycobacterium avium, as well as extracellular pathogen Candida albicans. This study demonstrates opposing roles for SNAP23 and SNAP25 in MR1 antigen presentation to MAIT cells, and extends our understanding of how SNAP family proteins regulate MR1 trafficking.