NAADP-mediated endosomal calcium signaling enables MR1 presentation of Mycobacterium tuberculosis 4464
Year: 2025
Type: article
Abstract: Description The immune system has developed specialized mechanisms to recognize intracellular pathogens such as Mycobacterium tuberculosis (Mtb). Major Histocompatibility Complex, Class I-Related molecule (MR1) is a conserved nonclassical antigen presenting molecule that presents ligands derived from Mtb riboflavin synthesis to MR1-restricted T cells (MR1Ts). While endosomal trafficking facilitates MR1 antigen presentation, the exact mechanisms by which MR1 loading of Mtb-derived ligands occurs are not known. We found that endosomal calcium signaling mediates MR1 antigen presentation during Mtb infection. Nicotinic acid adenine dinucleotide phosphate (NAADP) acts as a second messenger for lysosomal calcium release by activating two-pore calcium channels (TPCs). Interference with TPCs via siRNA-mediated knockdown or treatment with a selective NAADP antagonist reduces MR1 antigen presentation of Mtb-derived ligands. NAADP synthesis is catalyzed by NAD glycohydrolases or dual NADPH oxidases. Inhibition of NAD glycohydrolase activity with a quinolone carboxamide inhibitor reduces MR1 antigen presentation of Mtb-derived ligands. These data suggest this enzymatic activity is important. We are investigating candidate proteins that possess this enzymatic activity to further elucidate requirements for MR1 antigen presentation of Mtb-derived ligands. Together, these findings suggest a unique role for endosomal calcium sensing in the recognition of the Mtb-infected cell. Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)
Source: The Journal of Immunology
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416451568
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