Department of Biotherapy Center, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shen Zhen 518033, China.
Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China.
Exp Neurol. 2020 Jul;329:113303. doi: 10.1016/j.expneurol.2020.113303. Epub 2020 Apr 8.
Death-associated protein kinase 1 (DAPK1) is a key protein that mediates neuronal death in ischemic stroke. Although the substrates of DAPK1 and molecular signal in stroke have been gradually discovered, the modulation of DAPK1 itself is still unclear. Here we first reveal that Caytaxin, a brain-specific member of BCL2/adenovirus E1B -interacting protein (BNIP-2), increases and interacts with DAPK1 as early as 2 h after middle cerebral artery occlusion (MCAO) in the penumbra area of mouse brain. Furthermore, Caytaxin binds to DAPK1 at the presynaptic site and inhibits DAPK1 catalytic activity. Silencing Caytaxin by Caytaxin shRNA (Sh-Caytaxin) enhances DAPK1 activity, deteriorates neuronal apoptosis and brain injuries both in vivo and in vitro. Thus, elevating presynaptic Caytaxin could prevent neuronal apoptosis by inhibiting DAPK1 activation in the acute stage of ischemic stroke. Caytaxin may physiologically protect neuronal cells and represent a potential prevention and therapeutic target in the early phase of cerebral ischemic stroke.
死亡相关蛋白激酶 1（DAPK1）是一种介导缺血性中风神经元死亡的关键蛋白。尽管 DAPK1 的底物和中风中的分子信号已逐渐被发现，但 DAPK1 自身的调节仍不清楚。在这里，我们首先揭示了脑特异性 BCL2/腺病毒 E1B-相互作用蛋白（BNIP-2）家族成员 Caytaxin 在大脑中动脉阻塞（MCAO）后 2 小时即可在半暗区增加并与 DAPK1 相互作用。此外，Caytaxin 在突触前部位与 DAPK1 结合并抑制 DAPK1 的催化活性。用 Caytaxin shRNA（Sh-Caytaxin）沉默 Caytaxin 可增强 DAPK1 的活性，无论是在体内还是体外，均可加重神经元凋亡和脑损伤。因此，在缺血性中风的急性期，升高突触前 Caytaxin 可通过抑制 DAPK1 的激活来防止神经元凋亡。Caytaxin 可能在生理上保护神经元细胞，并代表脑缺血性中风早期的一个潜在预防和治疗靶点。
