Protein kinase C-θ participates in NF-κB activation induced by CD3-CD28 costimulation through selective activation of IκB kinase β
Protein kinase C-θ participates in NF-κB activation induced by CD3-CD28 costimulation through selective activation of IκB kinase β
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DOI：
10.1128/mcb.20.8.2933-2940.2000
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发表时间：
2000-04-01
影响因子：
5.3
通讯作者：
Greene, WC
中科院分区：
文献类型：
--
作者：
Lin, X;O'Mahony, A;Greene, WC
真核转录因子NF-κ B/Rel家族在炎症、抗凋亡和免疫应答的调节中起重要作用。NF-κ B被许多刺激物激活，包括用T细胞受体（TCR）-CD 3复合物和CD 28受体特异性配体共刺激T细胞。然而，从TCR-CD 3和CD 28表面受体传递这些共刺激信号，导致核NF-κ B表达的信号传导中间体尚未明确。我们现在发现，蛋白激酶C-θ（PKC-θ），一种新的PKC亚型，在CD 3-CD 28共刺激诱导的信号通路中起着核心作用，导致Jurkat T细胞中NF-κ B的活化。我们发现PKC-θ的组成型活性突变体的表达有效地诱导NK-κ B活化，并刺激来自白细胞介素-2基因的RE/AP复合增强子。相反，激酶缺陷突变体或反义PKC-θ的表达选择性抑制CD 3-CD 28共刺激，但不抑制肿瘤坏死因子α诱导的Jurkat T细胞中NF-κ B活化。PKC-θ对NF-κ B的诱导是通过在不存在可检测的IKK α刺激的情况下激活I κ B激酶β（IKK β）介导的。PKC-θ直接或间接地刺激IKK β的磷酸化，导致该酶的活化。总之，这些结果表明PKC-θ参与了导致NF-κ B B活化的CD 3-CD 28共刺激途径，这与涉及Cot和NF-κ B诱导激酶（NIK）的途径明显不同。NF-κ B的PKC-θ激活通过选择性诱导IKK β介导，而Cot和NIK依赖性途径涉及IKK α和IKK β的诱导。
The NF-kappa B/Rel family of eukaryotic transcription factors plays an essential role in the regulation of inflammatory, antiapoptotic, and immune responses. NF-kappa B is activated by many stimuli including costimulation of T cells with ligands specific for the T-cell receptor (TCR)-CD3 complex and CD28 receptors. However, the signaling intermediates that transduce these costimulatory signals from the TCR-CD3 and CD28 surface receptors leading to nuclear NF-kappa B expression are not well defined. We now show that protein kinase C-theta (PKC-theta), a novel PKC isoform, plays a central role in a signaling pathway induced by CD3-CD28 costimulation leading to activation of NF-kappa B in Jurkat T cells. We find that expression of a constitutively active mutant of PKC-theta potently induces NK-kappa B activation and stimulates the RE/AP composite enhancer from the interleukin-2 gene. Conversely, expression of a kinase-deficient mutant or antisense PKC-theta selectively inhibits CD3-CD28 costimulation, but not tumor necrosis factor alpha-induced activation of NF-kappa B in Jurkat T cells. The induction of NF-kappa B by PKC-theta is mediated through the activation of I kappa B kinase beta (IKK beta) in the absence of detectable IKK alpha stimulation. PKC-theta acts directly or indirectly to stimulate phosphorylation of IKK beta, leading to activation of this enzyme. Together, these results implicate PKC-theta in one pathway of CD3-CD28 costimulation leading to NF-kappa B activation that is apparently distinct from that involving Cot and NF-kappa B-inducing kinase (NIK). PKC-theta activation of NF-kappa B is mediated through the selective induction of IKK beta, while the Cot- and NIK-dependent pathway involves induction of both IKK alpha and IKK beta.