HIV-1 Tat-mediated activation of glycogen synthase kinase-3β contributes to Tat-mediated neurotoxicity
HIV-1 Tat-mediated activation of glycogen synthase kinase-3β contributes to Tat-mediated neurotoxicity
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DOI：
10.1046/j.1471-4159.1999.0730578.x
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发表时间：
1999-08-01
影响因子：
4.7
通讯作者：
Dewhurst, S
中科院分区：
文献类型：
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作者：
Maggirwar, SB;Tong, N;Dewhurst, S
人类免疫缺陷病毒1型（HIV-1）达特诱导神经元凋亡。为了研究促进这一过程的机制，我们研究了达特对糖原合成酶激酶-3 β（GSK-3 β）的影响，GSK-3 β是一种参与细胞凋亡调节的酶。向大鼠小脑颗粒神经元中加入达特导致GSK-3 β活性增加，这与蛋白表达的变化无关，并且可以通过加入GSK-3 β抑制剂（锂）来消除。共沉淀实验表明，达特可以与GSK-3 β结合，但直接将达特加入纯化的GSK-3 β中对酶活性没有影响，这表明达特的作用可能是间接介导的。由于血小板活化因子（PAF）受体的激活对于几种候选HIV-1神经毒素诱导神经元死亡至关重要，我们确定PAF是否也能激活GSK-3 β，将PAF应用于神经元培养物激活GSK-3 β，并与锂共孵育改善PAF诱导的神经元凋亡。这些发现与存在一种或多种可导致神经元中GSK-3 β激活的途径一致，并且它们表明这种酶的失调可能有助于HIV诱导的神经元凋亡。
Human immunodeficiency virus type 1 (HIV-1) Tat induces neuronal apoptosis. To examine the mechanism(s) that contribute to this process, we studied Tat's effects on glycogen synthase kinase-3 beta (GSK-3 beta), an enzyme that has been implicated in the regulation of apoptosis. Addition of Tat to rat cerebellar granule neurons resulted in an increase in GSK-3 beta activity, which was not associated with a change in protein expression and could be abolished by the addition of an inhibitor of GSK-3 beta (lithium). Lithium also enhanced neuronal survival following exposure to Tat, Coprecipitation experiments revealed that Tat can associate with GSK-3 beta, but direct addition of Tat to purified GSK-3 beta had no effect on enzyme activity, suggesting that Tat's effects might be mediated indirectly. As the activation of platelet activating factor (PAF) receptors is critical for the induction of neuronal death by several candidate HIV-1 neurotoxins, we determined whether PAF can also activate GSK-3 beta, Application of PAF to neuronal cultures activated GSK-3 beta, and coincubation with lithium ameliorated PAF-induced neuronal apoptosis. These findings are consistent with the existence of one or more pathways that can lead to GSK-3 beta activation in neurons, and they suggest that the dysregulation of this enzyme could contribute to HIV-induced neuronal apoptosis.