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IRAP通过驱动核糖体降解为脓毒性血栓形成期间的血小板激活补充能量。

IRAP Drives Ribosomal Degradation to Refuel Energy for Platelet Activation during Septic Thrombosis.

作者信息

Xu Baichuan, Ye Xianpeng, Sun Kangfu, Chen Liang, Wen Zhaoyang, Lan Qigang, Chen Jun, Chen Mo, Shen Mingqiang, Wang Song, Xu Yang, Zhang Xi, Zhao Jinghong, Wang Junping, Chen Shilei

机构信息

State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China.

Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, China.

出版信息

Adv Sci (Weinh). 2025 Apr;12(13):e2411914. doi: 10.1002/advs.202411914. Epub 2025 Jan 24.

DOI:10.1002/advs.202411914
PMID:39853919
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11967848/
Abstract

Platelets play crucial roles in multiple pathophysiological processes after energy-dependent activation. It is puzzling how such a small cellular debris has abundant energy supply. In this study, it is shown that insulin-regulated aminopeptidase (IRAP), a type II transmembrane protein, is a key regulator for platelet activation by promoting energy regeneration during septic thrombosis. Through interaction with certain endosome membrane proteins, IRAP can not only promote granule release, but also facilitate lysosomal degradation of theoretically discarded ribosomes in an mTORC1- and S-acylation-dependent manner in activated platelets. Plentiful amino acids obtained from IRAP-mediated ribophagy are recruited to aerobic glycolysis and then promote energy metabolism reprogramming, thereby producing abundant energy for platelet life extension and prolonged activation. Consequently, targeted blocking IRAP can dramatically alleviate platelet hyperactivation and septic thrombosis.

摘要

血小板在能量依赖性激活后的多种病理生理过程中发挥着关键作用。如此微小的细胞碎片如何拥有充足的能量供应，这令人费解。在本研究中，结果表明胰岛素调节氨肽酶（IRAP），一种II型跨膜蛋白，是脓毒症血栓形成过程中通过促进能量再生来调节血小板激活的关键因子。通过与某些内体膜蛋白相互作用，IRAP不仅可以促进颗粒释放，还能以mTORC1和S-酰化依赖的方式促进活化血小板中理论上被丢弃的核糖体的溶酶体降解。从IRAP介导的核糖体自噬中获得的大量氨基酸被用于有氧糖酵解，进而促进能量代谢重编程，从而为血小板的寿命延长和长时间激活产生充足的能量。因此，靶向阻断IRAP可显著减轻血小板过度激活和脓毒症血栓形成。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/5e0e08dddeab/ADVS-12-2411914-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/e44a30605cb2/ADVS-12-2411914-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/6be1d9c6cbd1/ADVS-12-2411914-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/3b488881f700/ADVS-12-2411914-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/f16feb4ad48f/ADVS-12-2411914-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/51aa37e8254c/ADVS-12-2411914-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/61dbd38b97a7/ADVS-12-2411914-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/5e0e08dddeab/ADVS-12-2411914-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/e44a30605cb2/ADVS-12-2411914-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/6be1d9c6cbd1/ADVS-12-2411914-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/3b488881f700/ADVS-12-2411914-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/f16feb4ad48f/ADVS-12-2411914-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/51aa37e8254c/ADVS-12-2411914-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/61dbd38b97a7/ADVS-12-2411914-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f475/11967848/5e0e08dddeab/ADVS-12-2411914-g008.jpg

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