GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway

Item Type:	Article
Title:	GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway
Creators Name:	Park, A.Y. and Leney-Greene, M. and Lynberg, M. and Gabrielski, J.Q. and Xu, X. and Schwarz, B. and Zheng, L. and Balasubramaniyam, A. and Ham, H. and Chao, B. and Zhang, Y. and Matthews, H.F. and Cui, J. and Yao, Y. and Kubo, S. and Chanchu, J.M. and Morawski, A.R. and Cook, S.A. and Jiang, P. and Ravell, J.C. and Cheng, Y.H. and George, A. and Faruqi, A. and Pagalilauan, A.M. and Bergerson, J.R.E. and Ganesan, S. and Chauvin, S.D. and Aluri, J. and Edwards-Hicks, J. and Bohrnsen, E. and Tippett, C. and Omar, H. and Xu, L. and Butcher, G.W. and Pascall, J. and Karakoc-Aydiner, E. and Kiykim, A. and Maecker, H. and Tezcan, İ. and Esenboga, S. and Heredia, R.J. and Akata, D. and Tekin, S. and Kara, A. and Kuloglu, Z. and Unal, E. and Kendirli, T. and Dogu, F. and Karabiber, E. and Atkinson, T.P. and Cochet, C. and Filhol, O. and Bosio, C.M. and Davis, M.M. and Lifton, R.P. and Pearce, E.L. and Daumke, O. and Aytekin, C. and Şahin, G.E. and Aksu, A.Ü. and Uzel, G. and Koneti Rao, V. and Sari, S. and Boztug, K. and Cagdas, D. and Haskologlu, S. and Ikinciogullari, A. and Schwefel, D. and Vilarinho, S. and Baris, S. and Ozen, A. and 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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