CKIP-1 is an intrinsic negative regulator of T-cell activation through an interaction with CARMA1.
CKIP-1 is an intrinsic negative regulator of T-cell activation through an interaction with CARMA1.
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DOI：
10.1371/journal.pone.0085762
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Takaori-Kondo A
中科院分区：
文献类型：
--
作者：
Sakamoto T;Kobayashi M;Tada K;Shinohara M;Io K;Nagata K;Iwai F;Takiuchi Y;Arai Y;Yamashita K;Shindo K;Kadowaki N;Koyanagi Y;Takaori-Kondo A
转录因子 NF-κB 在淋巴细胞激活和免疫反应的产生中起着关键的调节作用。 T 细胞受体 (TCR) 的刺激诱导 PKCθ 对 CARMA1 进行磷酸化，导致在脂筏处形成 CARMA1-Bcl10-MALT1 (CBM) 复合物，随后导致 NF-κB 激活。虽然已经报道了许多导致 NF-κB 激活的分子事件，但人们对这种激活如何受到负调控的了解还较少。我们使用诱变和互补克隆策略对 TCR 介导的 NF-κB 激活的负调节因子进行了基于细胞的筛选。在这里，我们发现酪蛋白激酶 2 相互作用蛋白 1 (CKIP-1) 抑制 PKCθ-CBM-NF-κB 信号传导。我们发现 CKIP-1 与 CARMA1 相互作用并与 PKCθ 竞争关联。我们进一步证实，CKIP-1 的 PH 结构域是与 CARMA1 关联及其抑制作用所必需的。 CKIP-1 抑制未刺激细胞中的 NF-κB 活性，并抑制由 PMA 或组成型活性 PKCθ 刺激诱导的 NF-κB 激活，但不抑制由 TNFα 刺激诱导的 NF-κB 激活。有趣的是，CKIP-1 不会抑制 CD3/CD28 共刺激诱导的 NF-κB 激活，从而导致 CKIP-1 从脂筏解离。这些数据表明 CKIP-1 有助于维持 NF-κB 活性的静息状态或防止 T 细胞因信号传导不足而被激活。总之，我们证明 CKIP-1 与 CARMA1 相互作用并对 PKCθ-CBM-NF-κB 信号传导具有抑制作用。
The transcription factor NF-κB plays a key regulatory role in lymphocyte activation and generation of immune response. Stimulation of T cell receptor (TCR) induces phosphorylation of CARMA1 by PKCθ, resulting in formation of CARMA1-Bcl10-MALT1 (CBM) complex at lipid rafts and subsequently leading to NF-κB activation. While many molecular events leading to NF-κB activation have been reported, it is less understood how this activation is negatively regulated. We performed a cell-based screening for negative regulators of TCR-mediated NF-κB activation, using mutagenesis and complementation cloning strategies. Here we show that casein kinase-2 interacting protein-1 (CKIP-1) suppresses PKCθ-CBM-NF-κB signaling. We found that CKIP-1 interacts with CARMA1 and competes with PKCθ for association. We further confirmed that a PH domain of CKIP-1 is required for association with CARMA1 and its inhibitory effect. CKIP-1 represses NF-κB activity in unstimulated cells, and inhibits NF-κB activation induced by stimulation with PMA or constitutively active PKCθ, but not by stimulation with TNFα. Interestingly, CKIP-1 does not inhibit NF-κB activation induced by CD3/CD28 costimulation, which caused dissociation of CKIP-1 from lipid rafts. These data suggest that CKIP-1 contributes maintenance of a resting state on NF-κB activity or prevents T cells from being activated by inadequate signaling. In conclusion, we demonstrate that CKIP-1 interacts with CARMA1 and has an inhibitory effect on PKCθ-CBM-NF-κB signaling.
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Lamason RL;Kupfer A;Pomerantz JL
通讯作者：
Pomerantz JL
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