美国国立卫生研究院Michael J. Lenardo课题发现，GIMAP5缺陷揭示哺乳动物神经酰胺驱动的长寿途径。2024年1月3日出版的《自然—免疫学》杂志发表了这一成果。

他们报告了一种新的人类遗传疾病，导致细胞衰老，肝脏和免疫功能障碍，以及早期死亡，这是由于GIMAP5的缺乏造成的，GIMAP5是一种在淋巴细胞和内皮细胞中选择性表达的进化保守的GTPase。他们发现GIMAP5限制长链神经酰胺(CERs)的病理积累，从而调节寿命。

GIMAP5通过与蛋白激酶CK2 (CK2)相互作用来控制CER丰度，从而减弱其激活CER合成酶的能力。抑制CK2和CER合成酶可通过防止CER过度积累和细胞退化来拯救GIMAP5缺陷T细胞。因此，GIMAP5控制着对哺乳动物免疫功能和健康至关重要的长寿保证途径。

研究人员表示，保持细胞的功能，非衰老状态是延长人类健康寿命的主要目标。模式生物揭示了长寿和衰老是由基因控制的，但基因如何在不同的哺乳动物组织中控制寿命尚不清楚。

附：英文原文

Title: GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway

Author: Park, Ann Y., Leney-Greene, Michael, Lynberg, Matthew, Gabrielski, Justin Q., Xu, Xijin, Schwarz, Benjamin, Zheng, Lixin, Balasubramaniyam, Arasu, Ham, Hyoungjun, Chao, Brittany, Zhang, Yu, Matthews, Helen F., Cui, Jing, Yao, Yikun, Kubo, Satoshi, Chanchu, Jean Michel, Morawski, Aaron R., Cook, Sarah A., Jiang, Ping, Ravell, Juan C., Cheng, Yan H., George, Alex, Faruqi, Aiman, Pagalilauan, Alison M., Bergerson, Jenna R. E., Ganesan, Sundar, Chauvin, Samuel D., Aluri, Jahnavi, Edwards-Hicks, Joy, Bohrnsen, Eric, Tippett, Caroline, Omar, Habib, Xu, Leilei, Butcher, Geoffrey W., Pascall, John, Karakoc-Aydiner, Elif, Kiykim, Ayca, Maecker, Holden, Tezcan, lhan, Esenboga, Saliha, Heredia, Raul Jimenez, Akata, Deniz, Tekin, Saban, Kara, Altan, Kuloglu, Zarife, Unal, Emel, Kendirli, Tanl, Dogu, Figen, Karabiber, Esra, Atkinson, T. Prescott, Cochet, Claude, Filhol, Odile, Bosio, Catherine M., Davis, Mark M., Lifton, Richard P., Pearce, Erika L., Daumke, Oliver

Issue&Volume: 2024-01-03

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.

DOI: 10.1038/s41590-023-01691-y

Source: https://www.nature.com/articles/s41590-023-01691-y