GIMAP5 regulates a lymphocyte longevity assurance pathway

Abstract Elucidating the molecular mechanisms of immunodeficiency diseases is a powerful approach to discovering new immunoregulatory pathways in humans. One such previously unknown pathway that GIMAP5, an evolutionarily conserved GTPase expressed T and NK lymphocytes, also known as gene mutated Biobreeding diabetic rat Sphinx lymphopenic mice. To better understand this disease association, we identified causative GIMAP5 mutations 17 individuals 9 kindreds with lymphopenia, liver disease, splenomegaly, thrombocytopenia, lymphadenopathy, lung infections, lymphoma. As mechanism action, now report controls pathological accumulation long chain ceramides. The ceramide synthase inhibitor, fumonisin B1, rescues GIMAP5-deficient cells from overaccumulation cell deterioration. Concordant these findings, induction death by exogenous C6-ceramides human blasts was reduced B1 overexpression. Our work reveals underlying long-chain mechanics opening opportunities for further metabolomic studies targets development therapeutics. This research supported NIAID Intramural Research Program NIH.