Rod-Derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic Glycolysis
Rod-Derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic Glycolysis
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DOI：
10.1016/j.cell.2015.03.023
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发表时间：
2015-05-07
期刊：
影响因子：
64.5
通讯作者：
Leveillard, Thierry
中科院分区：
文献类型：
--
作者：
Ait-Ali, Najate;Fridlich, Ram;Leveillard, Thierry
视杆细胞衍生视锥细胞活力因子（RdCVF）是由视杆细胞光感受器分泌的保护视锥细胞免于变性的无活性硫氧还蛋白。由于视网膜色素变性（RP）中的视锥细胞继发性丢失导致失明，因此给予RdCVF是治疗这种无法治疗的神经退行性疾病的有希望的疗法。在这里，我们研究了RdCVF在RP中的保护作用的机制。我们表明，RdCVF通过结合Basigin-1（BSG 1），一种由光感受器特异性表达的跨膜蛋白发挥作用。BSG 1与葡萄糖转运蛋白GLUT 1结合，导致进入视锥细胞的葡萄糖增加。增加的葡萄糖通过刺激有氧糖酵解促进视锥细胞存活。此外，RdCVF的错义突变导致其不能与BSG 1结合，刺激葡萄糖摄取，并防止RP模型中的继发性视锥细胞死亡。我们的数据揭示了一个全新的神经保护机制，通过刺激葡萄糖代谢。
Rod-derived cone viability factor (RdCVF) is an inactive thioredoxin secreted by rod photoreceptors that protects cones from degeneration. Because the secondary loss of cones in retinitis pigmentosa (RP) leads to blindness, the administration of RdCVF is a promising therapy for this untreatable neurodegenerative disease. Here, we investigated the mechanism underlying the protective role of RdCVF in RP. We show that RdCVF acts through binding to Basigin-1 (BSG1), a transmembrane protein expressed specifically by photoreceptors. BSG1 binds to the glucose transporter GLUT1, resulting in increased glucose entry into cones. Increased glucose promotes cone survival by stimulation of aerobic glycolysis. Moreover, a missense mutation of RdCVF results in its inability to bind to BSG1, stimulate glucose uptake, and prevent secondary cone death in a model of RP. Our data uncover an entirely novel mechanism of neuroprotection through the stimulation of glucose metabolism.