GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway

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Item Type:	Article
Title:	GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway
Creators Name:	Park, A.Y., Leney-Greene, M., Lynberg, M., Gabrielski, J.Q., Xu, X., Schwarz, B., Zheng, L., Balasubramaniyam, A., Ham, H., Chao, B., Zhang, Y., Matthews, H.F., Cui, J., Yao, Y., Kubo, S., Chanchu, J.M., Morawski, A.R., Cook, S.A., Jiang, P., Ravell, J.C., Cheng, Y.H., George, A., Faruqi, A., Pagalilauan, A.M., Bergerson, J.R.E., Ganesan, S., Chauvin, S.D., Aluri, J., Edwards-Hicks, J., Bohrnsen, E., Tippett, C., Omar, H., Xu, L., Butcher, G.W., Pascall, J., Karakoc-Aydiner, E., Kiykim, A., Maecker, H., Tezcan, İ., Esenboga, S., Heredia, R.J., Akata, D., Tekin, S., Kara, A., Kuloglu, Z., Unal, E., Kendirli, T., Dogu, F., Karabiber, E., Atkinson, T.P., Cochet, C., Filhol, O., Bosio, C.M., Davis, M.M., Lifton, R.P., Pearce, E.L., Daumke, O., Aytekin, C., Şahin, G.E., Aksu, A.Ü., Uzel, G., Koneti Rao, V., Sari, S., Boztug, K., Cagdas, D., Haskologlu, S., Ikinciogullari, A., Schwefel, D., Vilarinho, S., Baris, S., Ozen, A., Su, H.C. and Lenardo, M.J.
Abstract:	Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.
Keywords:	Ceramides, Endothelial Cells, GTP-Binding Proteins, Longevity, Animals, Mammals
Source:	Nature Immunology
ISSN:	1529-2908
Publisher:	Nature Publishing Group
Volume:	25
Number:	2
Page Range:	282-293
Date:	February 2024
Additional Information:	Erratum in: Nat Immunol. 2024
Official Publication:	https://doi.org/10.1038/s41590-023-01691-y
PubMed:	View item in PubMed

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