Involvement of PI 3 kinase/Akt-dependent Bad phosphorylation in Toxoplasma gondii-mediated inhibition of host cell apoptosis
Involvement of PI 3 kinase/Akt-dependent Bad phosphorylation in Toxoplasma gondii-mediated inhibition of host cell apoptosis
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DOI：
10.1016/j.exppara.2013.01.005
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发表时间：
2013-04-01
影响因子：
2.1
通讯作者：
Lee, Young-Ha
中科院分区：
文献类型：
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作者：
Quan, Juan-Hua;Cha, Guang-Ho;Lee, Young-Ha
弓形虫感染的细胞对各种凋亡刺激具有抗性，然而，促凋亡的BH 3-only Bad蛋白在弓形虫感染的细胞中的作用尚不清楚。与磷酸肌醇3-激酶（PI 3 K）-PKB/Akt途径相关的gondii对宿主细胞凋亡的抑制作用没有很好地描述。本文研究了Bad、Bax和PKB/Akt在T.用星形孢菌素（STS）或PI 3 K抑制剂处理的刚地氏感染和未感染的THP-1细胞。STS处理，不加T.弓形虫感染，与STS浓度成比例地降低THP-1细胞的生存力，并引发许多细胞死亡事件，如半胱天冬酶-3和-9活化、Bax易位、细胞色素c从宿主细胞线粒体释放到胞质溶胶中以及宿主细胞中的PARP裂解。然而，T.弓形虫感染消除了上述STS触发的线粒体凋亡事件。此外，T.体外和体内弓形虫感染均诱导PKB/Akt和Bad磷酸化，并以寄生虫负荷依赖的方式抑制Bax易位。PI 3 K抑制剂LY 294002和Wortmannin均阻断寄生虫诱导的PKB/Akt和Bad磷酸化。此外，用这些PI 3 K抑制剂预处理的THP-1细胞显示Bad磷酸化以剂量依赖性方式降低，随后不能抑制Bax易位，这些细胞也不能克服T. gondii施加的宿主细胞凋亡抑制。提示PI 3 K-PKB/Akt通路可能是T.弓形虫对宿主细胞凋亡和T.弓形虫使促凋亡Bad蛋白磷酸化以防止凋亡。(C)2013 Elsevier Inc. All rights reserved.
Toxoplasma gondii-infected cells are resistant to various apoptotic stimuli, however, the role of the proapoptotic BH3-only Bad protein in T. gondii-imposed inhibition of host cell apoptosis in connection with the phosphoinositide 3-kinase (PI3K)-PKB/Akt pathway was not well delineated. Here, we investigated the signaling patterns of Bad, Bax and PKB/Akt in T. gondii-infected and uninfected THP-1 cells treated with staurosporine (STS) or PI3K inhibitors. STS treatment, without T. gondii infection, reduced the viability of THP-1 cells in proportion to STS concentration and triggered many cellular death events such as caspase-3 and -9 activation, Bax translocation, cytochrome c release from host cell mitochondria into cytosol, and PARP cleavage in the host cell. However, T. gondii infection eliminated the STS-triggered mitochondrial apoptotic events described above. Additionally, T. gondii infection in vitro and in vivo induced the phosphorylation of PKB/Akt and Bad in a parasite-load-dependent manner which subsequently inhibited Bax translocation. The PI3K inhibitors, LY294002 and Wortmannin, both blocked parasite-induced phosphorylation of PKB/Akt and Bad. Furthermore, THP-1 cells pretreated with these PI3K inhibitors showed reduced phosphorylation of Bad in a dose-dependent manner and subsequently failed to inhibit the Bax translocation, also these cells also failed to overcome the T. gondii-imposed inhibition of host cell apoptosis. These data demonstrate that the PI3K-PKB/Akt pathway may be one of the major route for T. gondii in the prevention of host cell apoptosis and T. gondii phosphorylates the pro-apoptotic Bad protein to prevent apoptosis. (C) 2013 Elsevier Inc. All rights reserved.