HIV-1 Tat activates dual Nox pathways leading to independent activation of ERK and JNK MAP kinases
HIV-1 Tat activates dual Nox pathways leading to independent activation of ERK and JNK MAP kinases
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DOI：
10.1074/jbc.m704481200
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发表时间：
2007-12-28
影响因子：
4.8
通讯作者：
Terada, Lance S.
中科院分区：
文献类型：
--
作者：
Wu, Ru Feng;Ma, Zhenyi;Terada, Lance S.
人类免疫缺陷病毒1型TAT通过丝裂原活化蛋白(MAP)激酶对血管内皮细胞发挥多效性作用，但导致MAP激酶激活的信号通路尚不完全清楚。我们重点研究了TAT可能控制下游MAPK活性的近端通路。在2分钟内，TAT激活内皮细胞中的Ras和Rho GTP酶，导致ERK磷酸化10分钟。值得注意的是，rac1是RhoA下游激活所必需的，而rac1和RhoA都作用于RAS/ERK盒的上游。抗氧化剂和酶抑制剂二苯基碘可阻断ERK的磷酸化，但对典型的NOX2氧化酶的特异性干扰对ERK没有影响。相反，敲除新的氧化酶NOX4完全抑制了Rac1和RhoA下游依赖于TAT的RAS和ERK的激活。相反，对rac1、PAK1和NOX2的干扰可阻断JNK的磷酸化，而RhoA(N19)和NOX4的干扰不能阻断JNK的磷酸化。此外，敲除NOX2，而不是NOX4，阻止TAT诱导的细胞骨架重排，而敲除NOX4，但不是NOX2，阻止TAT依赖的增殖。因此，rac1将TAT信号分成两个分支，导致依赖于NOX4的RAS/ERK激活和依赖于NOX2的JNK激活。因此，TAT信号提供了一个对MAP激酶通路进行NOx特异性差异控制的例子。
Human immunodeficiency virus, type 1 Tat is known to exert pleiotropic effects on the vascular endothelium through mitogen-activated protein (MAP) kinases, although the signaling pathways leading to MAP kinase activation are incompletely understood. We focused on proximal pathways potentially governing downstream MAP kinase activity by Tat. Within 2 min, Tat activated both Ras and Rho GTPases in endothelial cells, leading to ERK phosphorylation by 10 min. Notably, Rac1 was necessary for downstream activation of RhoA and both Rac1 and RhoA acted upstream of the Ras/ERK cassette. Antioxidants and the oxidase inhibitor diphenylene iodonium blocked ERK phosphorylation, but specific interference with the canonical Nox2 oxidase had no effect on ERK. Instead, knock down of the novel oxidase Nox4 completely suppressed Tat-dependent Ras and ERK activation downstream of Rac1 and RhoA. Conversely, interference with Rac1, PAK1, and Nox2 blocked JNK phosphorylation, whereas RhoA(N19) and Nox4 knock down did not. Further, knock down of Nox2, but not Nox4, blocked Tat-induced cytoskeletal rearrangement, whereas knock down of Nox4, but not Nox2, blocked Tat-dependent proliferation. Rac1, therefore, bifurcates Tat signaling, leading to concurrent but separate Nox4-dependent Ras/ERK activation, and Nox2-dependent JNK activation. Tat signaling, therefore, provides an example of Nox-specific differential control of MAP kinase pathways.