激酶 IKKα 通过磷酸化调节分子 TAX1BP1 来抑制转录因子 NF-κB 的激活。
The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1.
机构信息
Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, Florida, USA.
出版信息
Nat Immunol. 2011 Jul 17;12(9):834-43. doi: 10.1038/ni.2066.
Abstract
In response to stimulation with proinflammatory cytokines, the deubiquitinase A20 inducibly interacts with the regulatory molecules TAX1BP1, Itch and RNF11 to form the A20 ubiquitin-editing complex. However, the molecular signal that coordinates the assembly of this complex has remained elusive. Here we demonstrate that TAX1BP1 was inducibly phosphorylated on Ser593 and Ser624 in response to proinflammatory stimuli. The kinase IKKα, but not IKKβ, was required for phosphorylation of TAX1BP1 and directly phosphorylated TAX1BP1 in response to stimulation with tumor necrosis factor (TNF) or interleukin 1 (IL-1). TAX1BP1 phosphorylation was pivotal for cytokine-dependent interactions among TAX1BP1, A20, Itch and RNF11 and downregulation of signaling by the transcription factor NF-κB. IKKα therefore serves a key role in the negative feedback of NF-κB canonical signaling by orchestrating assembly of the A20 ubiquitin-editing complex to limit inflammatory gene activation.
摘要
在受到促炎细胞因子刺激时，去泛素化酶 A20 可诱导性地与调节分子 TAX1BP1、Itch 和 RNF11 相互作用，形成 A20 泛素编辑复合物。然而，协调该复合物组装的分子信号一直难以捉摸。在这里，我们证明了 TAX1BP1 在受到促炎刺激时可被诱导性地上调丝氨酸 593 和丝氨酸 624 磷酸化。激酶 IKKα（而非 IKKβ）对于 TAX1BP1 的磷酸化以及在受到肿瘤坏死因子（TNF）或白细胞介素 1（IL-1）刺激时对 TAX1BP1 的直接磷酸化是必需的。TAX1BP1 磷酸化对于细胞因子依赖性的 TAX1BP1、A20、Itch 和 RNF11 之间的相互作用以及转录因子 NF-κB 信号转导的下调至关重要。因此，IKKα 通过协调 A20 泛素编辑复合物的组装来限制炎症基因的激活，从而在 NF-κB 经典信号转导的负反馈中发挥关键作用。
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