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首页> 外文期刊>Molecular and Cellular Biology >Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation.
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Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation.

机译：IκB alpha中的信号响应域与NF-κB激活的多种途径偶联。

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摘要

The eukaryotic transcription factor NF-kappa B plays a central role in the induced expression of human immunodeficiency virus type 1 and in many aspects of the genetic program mediating normal T-cell activation and growth. The nuclear activity of NF-kappa B is tightly regulated from the cytoplasmic compartment by an inhibitory subunit called I kappa B alpha. This cytoplasmic inhibitor is rapidly phosphorylated and degraded in response to a diverse set of NF-kappa B-inducing agents, including T-cell mitogens, proinflammatory cytokines, and viral transactivators such as the Tax protein of human T-cell leukemia virus type 1. To explore these I kappa B alpha-dependent mechanisms for NF-kappa B induction, we identified novel mutants of I kappa B alpha that uncouple its inhibitory and signal-transducing functions in human T lymphocytes. Specifically, removal of the N-terminal 36 amino acids of I kappa B alpha failed to disrupt its ability to form latent complexes with NF-kappa B in the cytoplasm. However, this deletion mutation prevented the induced phosphorylation, degradative loss, and functional release of I kappa B alpha from NF-kappa B in Tax-expressing cells. Alanine substitutions introduced at two serine residues positioned within this N-terminal regulatory region of I kappa B alpha also yielded constitutive repressors that escaped from Tax-induced turnover and that potently inhibited immune activation pathways for NF-kappa B induction, including those initiated from antigen and cytokine receptors. In contrast, introduction of a phosphoserine mimetic at these sites rectified this functional defect, a finding consistent with a causal linkage between the phosphorylation status and proteolytic stability of this cytoplasmic inhibitor. Together, these in vivo studies define a critical signal response domain in I kappa B alpha that coordinately controls the biologic activities of I kappa B alpha and NF-kappa B in response to viral and immune stimuli.
机译：真核转录因子NF-κB在人类免疫缺陷病毒1型的诱导表达以及介导正常T细胞活化和生长的遗传程序的许多方面起着核心作用。 NF-κB的核活性由称为Ikappa B alpha的抑制性亚基从细胞质区严格调控。这种细胞质抑制剂会被多种NF-κB诱导剂迅速磷酸化并降解，这些诱导剂包括T细胞促分裂原，促炎细胞因子和病毒反式激活因子，例如1型人类T细胞白血病病毒的Tax蛋白。为了探索这些IκBα依赖性的NFκB诱导机制，我们鉴定了IκBα的新型突变体，该突变体在人类T淋巴细胞中解耦了其抑制和信号传导功能。具体而言，IκBα的N末端36个氨基酸的去除不能破坏其在细胞质中与NF-κB形成潜在复合物的能力。然而，这种缺失突变阻止了在表达税的细胞中IκBα从NF-κB的诱导的磷酸化，降解损失和功能性释放。在位于IκBαN末端调节区内的两个丝氨酸残基处引入的丙氨酸取代也产生组成型阻遏物，其逃避了Tax诱导的周转，并有效抑制了NF-κB诱导的免疫激活途径，包括那些由抗原引发的和细胞因子受体。相反，在这些位点引入磷酸丝氨酸模拟物可纠正此功能缺陷，这一发现与该细胞质抑制剂的磷酸化状态和蛋白水解稳定性之间的因果关系一致。总之，这些体内研究在IκB alpha中定义了一个关键的信号响应域，该域协调控制IκB alpha和NF-κB对病毒和免疫刺激的生物学活性。

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