Critical role for Akt1 in the modulation of apoptotic phosphatidylserine exposure and microglial activation
Critical role for Akt1 in the modulation of apoptotic phosphatidylserine exposure and microglial activation
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DOI：
10.1124/mol.64.3.557
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发表时间：
2003-09-01
影响因子：
3.6
通讯作者：
Maiese, K
中科院分区：
文献类型：
--
作者：
Kang, JQ;Chong, ZZ;Maiese, K
神经退行性疾病的生物学靶点主要集中在细胞完整性的内在维持和吞噬细胞处置的外在预防上，这为治疗干预提供了最大的希望。蛋白激酶B(Akt1)是一种与细胞生长和存活密切相关的丝氨酸-苏氨酸激酶，在解决神经元损伤的内在和外在机制方面具有很强的潜力。我们证明，在分化的SH-SY5Y神经细胞中过表达具有结构性活性的Akt1(肉豆蔻酰化Akt1)可以提供内在的细胞保护，防止基因组DNA的凋亡和膜磷脂酰丝氨酸(PS)的暴露。将编码有显性缺失的Akt1的质粒导入SH-SY5Y细胞后，细胞保护作用消失，这表明Akt1的激活是必要的，也是防止细胞凋亡破坏的充分条件。神经细胞膜PS的凋亡暴露为Akt1提供了一条独特的途径来提供外部细胞保护和阻断小胶质细胞的激活，因为单独与抗PS受体中和抗体共同处理也可以防止小胶质细胞的增殖。AKT1通过特异性地抑制与线粒体膜电位和细胞色素c释放有关的caspase3、8和9样活性来维持核DNA的完整性和膜PS暴露。我们的工作阐明了Akt1通过一系列半胱氨酸蛋白酶途径维持细胞完整性的新能力，并通过调节膜PS残基外化来独特地调节小胶质细胞的激活。
Biological targets for neurodegenerative disease that focus on the intrinsic maintenance of cellular integrity and the extrinsic prevention of phagocytic cellular disposal offer the greatest promise for therapeutic intervention. Protein kinase B (Akt1), a serine-threonine kinase closely involved in cell growth and survival, offers a strong potential to address both intrinsic and extrinsic mechanisms of neuronal injury. We demonstrate that overexpression of a constitutively active form of Akt1 (myristoylated Akt1) in differentiated SH-SY5Y neuronal cells provides intrinsic cellular protection against apoptotic genomic DNA destruction and membrane phosphatidylserine (PS) exposure. Transfection of SH-SY5Y cells with a plasmid encoding a kinase-deficient dominant-negative Akt1 eliminates cytoprotection, suggesting that activation of Akt1 is necessary and sufficient to prevent apoptotic destruction. Apoptotic neuronal membrane PS exposure provides a unique pathway for Akt1 to offer extrinsic cellular protection and block microglial activation, because independent cotreatment with an anti-PS receptor neutralizing antibody could also prevent microglial proliferation. Akt1 maintains nuclear DNA integrity and membrane PS exposure through the specific inhibition of caspase 3-, 8-, and 9-like activities that were linked to mitochondrial membrane potential and cytochrome c release. Our work elucidates a novel capacity for Akt1 to maintain cellular integrity through a series of cysteine protease pathways and to uniquely regulate microglial activation through the modulation of membrane PS residue externalization.