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GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway.

Ann Y ParkMichael Leney-GreeneMatthew LynbergJustin Q GabrielskiXijin XuBenjamin SchwarzLixin ZhengArasu BalasubramaniyamHyoungjun HamBrittany ChaoYu ZhangHelen F MatthewsJing CuiYikun YaoYasuyuki TodorokiJean Michel ChanchuAaron R MorawskiSarah A CookPing JiangJuan C RavellYan H ChengAlex GeorgeAiman J FaruqiAlison M PagalilauanJenna R E BergersonSundar GanesanSamuel D ChauvinJahnavi AluriJoy Edwards-HicksEric BohrnsenCaroline TippettHabib OmarLeilei XuGeoffrey W ButcherJohn PascallElif Karakoc-AydinerAyca KiykimHolden Terry Maeckerİlhan TezcanSaliha EsenbogaRaul Jimenez HerediaDeniz AkataŞaban TekİnAltan KaraZarife KulogluEmel UnalTanıl KendirliFigen DoguEsra KarabiberT Prescott AtkinsonClaude CochetOdile Filhol-CochetCatherine M BosioMark M DavisRichard P LiftonErika L PearceOliver DaumkeCaner AytekinGülseren Evirgen ŞahinAysel Ünlüsoy AksuGulbu UzelV Koneti RaoSinan SariBuket DalgıçKaan BoztugDeniz CagdasZehra Şule HaskoloğluAydan IkinciogullariDavid SchwefelSilvia VilarinhoSafa BarışAhmet OzenHelen C SuMichael J Lenardo
Published in: Nature immunology (2024)
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.
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