GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway

Ann Y. Park; Michael Leney-Greene; Matthew Lynberg; Justin Q. Gabrielski; Xijin Xu; Benjamin Schwarz; Lixin Zheng; Arasu Balasubramaniyam; Hyoungjun Ham; Brittany Chao; Yu Zhang; Helen F. Matthews; Jing Cui; Yikun Yao; Satoshi Kubo; Jean Michel Chanchu; Aaron R. Morawski; Sarah A. Cook; Ping Jiang; Juan C. Ravell; Yan H. Cheng; Alex George; Aiman Faruqi; Alison M. Pagalilauan; Jenna R.E. Bergerson; Sundar Ganesan; Samuel D. Chauvin; Jahnavi Aluri; Joy Edwards-Hicks; Eric Bohrnsen; Caroline Tippett; Habib Omar; Leilei Xu; Geoffrey W. Butcher; John Pascall; Elif Karakoc-Aydiner; Ayca Kiykim; Holden Maecker; İlhan Tezcan; Saliha Esenboga; Raul Jimenez Heredia; Deniz Akata; Saban Tekin; Altan Kara; Zarife Kuloglu; Emel Unal; Tanıl Kendirli; Figen Dogu; Esra Karabiber; T. Prescott Atkinson; Claude Cochet; Odile Filhol; Catherine M. Bosio; Mark M. Davis; Richard P. Lifton; Erika L. Pearce; Oliver Daumke; Caner Aytekin; Gülseren Evirgen Şahin; Aysel Ünlüsoy Aksu; Gulbu Uzel; V. Koneti Rao; Sinan Sari; Kaan Boztug; Deniz Cagdas; Sule Haskologlu; Aydan Ikinciogullari; David Schwefel; Silvia Vilarinho; Safa Baris; Ahmet Ozen; Helen C. Su; Michael J. Lenardo

doi:10.1038/s41590-023-01691-y

GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway

Ann Y. Park, Michael Leney-Greene, Matthew Lynberg, Justin Q. Gabrielski, Xijin Xu, Benjamin Schwarz, Lixin Zheng, Arasu Balasubramaniyam, Hyoungjun Ham, Brittany Chao, Yu Zhang, Helen F. Matthews, Jing Cui, Yikun Yao, Satoshi Kubo, Jean Michel Chanchu, Aaron R. Morawski, Sarah A. Cook, Ping Jiang, Juan C. RavellYan H. Cheng, Alex George, Aiman Faruqi, Alison M. Pagalilauan, Jenna R.E. Bergerson, Sundar Ganesan, Samuel D. Chauvin, Jahnavi Aluri, Joy Edwards-Hicks, Eric Bohrnsen, Caroline Tippett, Habib Omar, Leilei Xu, Geoffrey W. Butcher, John Pascall, Elif Karakoc-Aydiner, Ayca Kiykim, Holden Maecker, İlhan Tezcan, Saliha Esenboga, Raul Jimenez Heredia, Deniz Akata, Saban Tekin, Altan Kara, Zarife Kuloglu, Emel Unal, Tanıl Kendirli, Figen Dogu, Esra Karabiber, T. Prescott Atkinson, Claude Cochet, Odile Filhol, Catherine M. Bosio, Mark M. Davis, Richard P. Lifton, Erika L. Pearce, Oliver Daumke, Caner Aytekin, Gülseren Evirgen Şahin, Aysel Ünlüsoy Aksu, Gulbu Uzel, V. Koneti Rao, Sinan Sari, Kaan Boztug, Deniz Cagdas, Sule Haskologlu, Aydan Ikinciogullari, David Schwefel, Silvia Vilarinho, Safa Baris, Ahmet Ozen, Helen C. Su, Michael J. Lenardo

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	282-293
Number of pages	12
Journal	Nature Immunology
Volume	25
Issue number	2
DOIs	https://doi.org/10.1038/s41590-023-01691-y
State	Published - Feb 2024

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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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., ... Lenardo, M. J. (2024). GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway. Nature Immunology, 25(2), 282-293. https://doi.org/10.1038/s41590-023-01691-y

Park, AY, Leney-Greene, M, Lynberg, M, Gabrielski, JQ, Xu, X, Schwarz, B, Zheng, L, Balasubramaniyam, A, Ham, H, Chao, B, Zhang, Y, Matthews, HF, Cui, J, Yao, Y, Kubo, S, Chanchu, JM, Morawski, AR, Cook, SA, Jiang, P, Ravell, JC, Cheng, YH, George, A, Faruqi, A, Pagalilauan, AM, Bergerson, JRE, Ganesan, S, Chauvin, SD, Aluri, J, Edwards-Hicks, J, Bohrnsen, E, Tippett, C, Omar, H, Xu, L, Butcher, GW, Pascall, J, Karakoc-Aydiner, E, Kiykim, A, Maecker, H, Tezcan, İ, Esenboga, S, Heredia, RJ, Akata, D, Tekin, S, Kara, A, Kuloglu, Z, Unal, E, Kendirli, T, Dogu, F, Karabiber, E, Atkinson, TP, Cochet, C, Filhol, O, Bosio, CM, Davis, MM, Lifton, RP, Pearce, EL, Daumke, O, Aytekin, C, Şahin, GE, Aksu, AÜ, Uzel, G, Koneti Rao, V, Sari, S, Boztug, K, Cagdas, D, Haskologlu, S, Ikinciogullari, A, Schwefel, D, Vilarinho, S, Baris, S, Ozen, A, Su, HC & Lenardo, MJ 2024, 'GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway', Nature Immunology, vol. 25, no. 2, pp. 282-293. https://doi.org/10.1038/s41590-023-01691-y

@article{028893c46c7d4599b27a41668c6389de,

title = "GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway",

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.",

author = "Park, {Ann Y.} and Michael Leney-Greene and Matthew Lynberg and Gabrielski, {Justin Q.} and Xijin Xu and Benjamin Schwarz and Lixin Zheng and Arasu Balasubramaniyam and Hyoungjun Ham and Brittany Chao and Yu Zhang and Matthews, {Helen F.} and Jing Cui and Yikun Yao and Satoshi Kubo and Chanchu, {Jean Michel} and Morawski, {Aaron R.} and Cook, {Sarah A.} and Ping Jiang and Ravell, {Juan C.} and Cheng, {Yan H.} and Alex George and Aiman Faruqi and Pagalilauan, {Alison M.} and Bergerson, {Jenna R.E.} and Sundar Ganesan and Chauvin, {Samuel D.} and Jahnavi Aluri and Joy Edwards-Hicks and Eric Bohrnsen and Caroline Tippett and Habib Omar and Leilei Xu and Butcher, {Geoffrey W.} and John Pascall and Elif Karakoc-Aydiner and Ayca Kiykim and Holden Maecker and İlhan Tezcan and Saliha Esenboga and Heredia, {Raul Jimenez} and Deniz Akata and Saban Tekin and Altan Kara and Zarife Kuloglu and Emel Unal and Tanıl Kendirli and Figen Dogu and Esra Karabiber and Atkinson, {T. Prescott} and Claude Cochet and Odile Filhol and Bosio, {Catherine M.} and Davis, {Mark M.} and Lifton, {Richard P.} and Pearce, {Erika L.} and Oliver Daumke and Caner Aytekin and {\c S}ahin, {G{\"u}lseren Evirgen} and Aksu, {Aysel {\"U}nl{\"u}soy} and Gulbu Uzel and {Koneti Rao}, V. and Sinan Sari and Kaan Boztug and Deniz Cagdas and Sule Haskologlu and Aydan Ikinciogullari and David Schwefel and Silvia Vilarinho and Safa Baris and Ahmet Ozen and Su, {Helen C.} and Lenardo, {Michael J.}",

note = "Publisher Copyright: {\textcopyright} 2024, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2024",

month = feb,

doi = "10.1038/s41590-023-01691-y",

language = "English (US)",

volume = "25",

pages = "282--293",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "2",

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TY - JOUR

T1 - GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway

AU - Park, Ann Y.

AU - Leney-Greene, Michael

AU - Lynberg, Matthew

AU - Gabrielski, Justin Q.

AU - Xu, Xijin

AU - Schwarz, Benjamin

AU - Zheng, Lixin

AU - Balasubramaniyam, Arasu

AU - Ham, Hyoungjun

AU - Chao, Brittany

AU - Zhang, Yu

AU - Matthews, Helen F.

AU - Cui, Jing

AU - Yao, Yikun

AU - Kubo, Satoshi

AU - Chanchu, Jean Michel

AU - Morawski, Aaron R.

AU - Cook, Sarah A.

AU - Jiang, Ping

AU - Ravell, Juan C.

AU - Cheng, Yan H.

AU - George, Alex

AU - Faruqi, Aiman

AU - Pagalilauan, Alison M.

AU - Bergerson, Jenna R.E.

AU - Ganesan, Sundar

AU - Chauvin, Samuel D.

AU - Aluri, Jahnavi

AU - Edwards-Hicks, Joy

AU - Bohrnsen, Eric

AU - Tippett, Caroline

AU - Omar, Habib

AU - Xu, Leilei

AU - Butcher, Geoffrey W.

AU - Pascall, John

AU - Karakoc-Aydiner, Elif

AU - Kiykim, Ayca

AU - Maecker, Holden

AU - Tezcan, İlhan

AU - Esenboga, Saliha

AU - Heredia, Raul Jimenez

AU - Akata, Deniz

AU - Tekin, Saban

AU - Kara, Altan

AU - Kuloglu, Zarife

AU - Unal, Emel

AU - Kendirli, Tanıl

AU - Dogu, Figen

AU - Karabiber, Esra

AU - Atkinson, T. Prescott

AU - Cochet, Claude

AU - Filhol, Odile

AU - Bosio, Catherine M.

AU - Davis, Mark M.

AU - Lifton, Richard P.

AU - Pearce, Erika L.

AU - Daumke, Oliver

AU - Aytekin, Caner

AU - Şahin, Gülseren Evirgen

AU - Aksu, Aysel Ünlüsoy

AU - Uzel, Gulbu

AU - Koneti Rao, V.

AU - Sari, Sinan

AU - Boztug, Kaan

AU - Cagdas, Deniz

AU - Haskologlu, Sule

AU - Ikinciogullari, Aydan

AU - Schwefel, David

AU - Vilarinho, Silvia

AU - Baris, Safa

AU - Ozen, Ahmet

AU - Su, Helen C.

AU - Lenardo, Michael J.

PY - 2024/2

Y1 - 2024/2

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85181246697&partnerID=8YFLogxK

U2 - 10.1038/s41590-023-01691-y

DO - 10.1038/s41590-023-01691-y

M3 - Article

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AN - SCOPUS:85181246697

SN - 1529-2908

VL - 25

SP - 282

EP - 293

JO - Nature Immunology

JF - Nature Immunology

IS - 2

ER -

GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway

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