GIMAP5 deficiency reveals a human cellular longevity assurance pathway

Abstract

Abstract Studies in model organisms have revealed that lifespan and senescence are genetically controlled, but how cellular longevity assurance pathways are regulated is unknown. Here, we report new insights into cell longevity and senescence through the investigation of a novel disease caused by mutations in GTPase of the immunity-associated protein 5 (GIMAP5). We identified 17 affected individuals in 9 kindreds with lymphopenia, liver disease, splenomegaly, thrombocytopenia, lymphadenopathy, lung infections, and lymphoma. GIMAP5is highly expressed in T and NK lymphocytes as well as endothelial cells (EC) and is famous as the gene mutated in the Biobreeding diabetic rat and Sphinx lymphopenic mice. Given the strong disease association, the mechanism of GIMAP5 is an important biological and medical question. We found that loss of GIMAP5 leads to the uncontrolled accumulation of long chain ceramides, which is associated with premature senescence and death of lymphocytes, resulting in severe and recurrent infections in patients. We further showed that Gimap5 deficiency in mice increases senescence markers in T cells and ECs of the lung and liver, suggesting that GIMAP5 is involved in the senescence mechanisms affecting multiple tissues. Therefore, our results illustrate the role of the GIMAP5 regulatory pathway in cell longevity and senescence and reveal new molecular targets for increasing the healthy functional lifespan of human cells. This research was supported by the Intramural Research Program of NIAID, NIH. This research was supported by the Intramural Research Program of NIAID, NIH.