Zhu Zhihui, Li Rongyu, Stricker Rolf, Reiser Georg
Institut für Neurobiochemie (Institut für Inflammation und Neurodegeneration), Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Leipziger Straße 44, Magdeburg 39120, Germany.
Institut für Neurobiochemie (Institut für Inflammation und Neurodegeneration), Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Leipziger Straße 44, Magdeburg 39120, Germany.
Brain Res. 2015 Sep 16;1620:17-28. doi: 10.1016/j.brainres.2015.05.011. Epub 2015 May 18.
α-Crystallin with two isoforms, αA-crystallin (HSPB4) and αB-crystallin (HSPB5), is found in eye lens, spleen, lung, kidney, cornea, skin, but also in brain. Several studies revealed roles of αA/αB-crystallin in regulating cell viability and protection in the central nervous system. We previously demonstrated that α-crystallin serves as an intracellular protectant in astrocytes. Compared to well-studied intracellular functions of α-crystallin, there is limited proof for the role of α-crystallin as extracellular protectant. In order to clarify protective effects of extracellular αA/αB-crystallin, we exposed astrocytes to the toxic agents, staurosporine or C2-ceramide, or serum-starvation in the presence of αA/αB-crystallin. Extracellular αA/αB-crystallin protected astrocytes from staurosporine- and C2-ceramide-induced cell death. In addition, extracellular αB-crystallin/HSPB5 effectively promoted astrocytes viability through phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinases (p38) and c-Jun N-terminal kinases (JNK) signaling pathways under serum-deprivation. Furthermore, αB-crystallin/HSPB5 decreases the staurosporine-mediated cleavage of caspase 3 through PI3K/Akt signaling preventing apoptosis of astrocytes. Thus, the current study indicates that extracellular αA/αB-crystallin protects astrocytes exposed to various harmful stimuli. Furthermore, application of αB-crystallin/HSPB5 to isolated rat brain mitochondria inhibits ROS generation induced by complex III inhibition with Antimycin A.
α-晶体蛋白有两种亚型，即αA-晶体蛋白（HSPB4）和αB-晶体蛋白（HSPB5），存在于眼晶状体、脾脏、肺、肾脏、角膜、皮肤中，也存在于大脑中。多项研究揭示了αA/αB-晶体蛋白在调节中枢神经系统细胞活力和保护方面的作用。我们之前证明α-晶体蛋白在星形胶质细胞中作为一种细胞内保护剂。与对α-晶体蛋白深入研究的细胞内功能相比，α-晶体蛋白作为细胞外保护剂的作用证据有限。为了阐明细胞外αA/αB-晶体蛋白的保护作用，我们在有αA/αB-晶体蛋白存在的情况下，将星形胶质细胞暴露于毒剂、星形孢菌素或C2-神经酰胺，或血清饥饿状态下。细胞外αA/αB-晶体蛋白保护星形胶质细胞免受星形孢菌素和C2-神经酰胺诱导的细胞死亡。此外，细胞外αB-晶体蛋白/HSPB5在血清剥夺条件下通过磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）/雷帕霉素哺乳动物靶蛋白（mTOR）和细胞外信号调节激酶1/2（ERK1/2）、p38丝裂原活化蛋白激酶（p38）和c-Jun氨基末端激酶（JNK）信号通路有效促进星形胶质细胞活力。此外，αB-晶体蛋白/HSPB5通过PI3K/Akt信号通路减少星形孢菌素介导的半胱天冬酶3的切割，防止星形胶质细胞凋亡。因此，当前研究表明细胞外αA/αB-晶体蛋白保护暴露于各种有害刺激的星形胶质细胞。此外，将αB-晶体蛋白/HSPB5应用于分离的大鼠脑线粒体可抑制抗霉素A抑制复合物III诱导的活性氧生成。
