Brain endothelial PTEN/AKT/NEDD4-2/MFSD2A axis regulates blood-brain barrier permeability
Brain endothelial PTEN/AKT/NEDD4-2/MFSD2A axis regulates blood-brain barrier permeability
复制标题
DOI：
10.1016/j.celrep.2021.109327
复制
发表时间：
2021-07-06
期刊：
影响因子：
8.8
通讯作者：
Yang, Xiao
中科院分区：
文献类型：
--
作者：
Cui, Yaxiong;Wang, Yanxiao;Yang, Xiao
低水平的跨细胞反应是脑血管内皮细胞(ECs)的一个独特特征，确保了限制性的血脑屏障(BBB)通透性。主要促进剂超家族结构域2a(MFSD2a)是血脑屏障功能的关键调节因子，通过抑制小凹介导的细胞转运而发挥作用。然而，在BBB中调节MFSD2A的机制几乎没有被探索过。在这里，我们表明，脑血管EC特异性的Pten(磷酸酶和张力蛋白同源)的缺失导致MFSD2A的减少，导致囊泡跨细胞作用的急剧增加，导致血脑屏障跨细胞通透性的增加。在机制上，AKT信号抑制E3泛素连接酶NEDD4-2介导的MFSD2A的降解。一贯地，脑血管Nedd4-2过表达降低MFSD2A水平，增加细胞转运，并损害血脑屏障通透性，概括了Pten缺陷小鼠的表型。此外，Akt缺失降低了Pten突变小鼠的磷酸化NEDD4-2水平，恢复了MFSD2A水平，并使血脑屏障通透性正常化。综上所述，我们的工作揭示了PTEN/AKT/NEDD4-2/MFSD2A轴在调节血脑屏障通透性中的重要生理功能。
The low level of transcytosis is a unique feature of cerebrovascular endothelial cells (ECs), ensuring restrictive blood-brain barrier (BBB) permeability. Major facilitator superfamily domain-containing 2a (MFSD2A) is a key regulator of the BBB function by suppressing caveolae-mediated transcytosis. However, the mechanisms regulating MFSD2A at the BBB have been barely explored. Here, we show that cerebrovascular EC-specific deletion of Pten (phosphatase and tensin homolog) results in a dramatic increase in vesicular transcytosis by the reduction of MFSD2A, leading to increased transcellular permeability of the BBB. Mechanistically, AKT signaling inhibits E3 ubiquitin ligase NEDD4-2-mediated MFSD2A degradation. Consistently, cerebrovascular Nedd4-2 overexpression decreases MFSD2A levels, increases transcytosis, and impairs BBB permeability, recapitulating the phenotypes of Pten-deficient mice. Furthermore, Akt deletion decreases phosphorylated NEDD4-2 levels, restores MFSD2A levels, and normalizes BBB permeability in Pten-mutant mice. Altogether, our work reveals the essential physiological function of the PTEN/AKT/NEDD4-2/MFSD2A axis in the regulation of BBB permeability.