Postrepression activation of NF-kappaB requires the amino-terminal nuclear export signal specific to IkappaBalpha.
Postrepression activation of NF-kappaB requires the amino-terminal nuclear export signal specific to IkappaBalpha.
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发表时间：
2001
影响因子：
5.3
通讯作者：
T. Huang;S. Miyamoto
中科院分区：
文献类型：
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作者：
T. Huang;S. Miyamoto
哺乳动物细胞中最突出的NF-κ B靶基因之一是编码其抑制蛋白之一IkappaB α的基因。IkappaB α的合成增加导致核NF-κ B活性的诱导后抑制。然而，目前尚不清楚为什么在多个IkappaB家族成员中，IkappaB alpha参与了这一过程，以及这种反馈调节除了终止NF-κ B活性之外还有什么意义。在这里，我们报告了一个重要的IkappaBa的特定功能，其氨基末端核输出序列（N-NES）。IkappaB alpha N-NES对于核NF-kappaB的诱导后输出是必要的，这是重新建立NF-kappaB快速重新激活的允许条件的关键事件。我们发现，虽然IkappaBalpha和另一个IkappaB成员，IkappaBbeta，可以进入细胞核和抑制NF-κ B DNA结合活性在诱导后阶段，只有IkappaBalpha允许核NF-κ B的有效出口。此外，将IkappaB β的N-末端区域交换为相应的IkappaB α序列足以使IkappaB嵌合蛋白在诱导后状态期间类似于IkappaB α输出NF-κ B。我们的研究结果提供了一个机制解释为什么IkappaB α，而不是其他IkappaB成员是至关重要的NF-κ B的后抑制激活。我们认为这种IkappaBa特异性功能对于某些需要迅速重新激活NF-κ B的生理和病理条件是重要的。
One of the most prominent NF-kappaB target genes in mammalian cells is the gene encoding one of its inhibitor proteins, IkappaBalpha. The increased synthesis of IkappaBalpha leads to postinduction repression of nuclear NF-kappaB activity. However, it is unknown why IkappaBalpha, among multiple IkappaB family members, is involved in this process and what significance this feedback regulation has beyond terminating NF-kappaB activity. Herein, we report an important IkappaBalpha-specific function dictated by its amino-terminal nuclear export sequence (N-NES). The IkappaBalpha N-NES is necessary for the postinduction export of nuclear NF-kappaB, which is a critical event in reestablishing a permissive condition for NF-kappaB to be rapidly reactivated. We show that although IkappaBalpha and another IkappaB member, IkappaBbeta, can enter the nucleus and repress NF-kappaB DNA-binding activity during the postinduction phase, only IkappaBalpha allows the efficient export of nuclear NF-kappaB. Moreover, swapping the N-terminal region of IkappaBbeta for the corresponding IkappaBalpha sequence is sufficient for the IkappaB chimera protein to export NF-kappaB similarly to IkappaBalpha during the postinduction state. Our findings provide a mechanistic explanation of why IkappaBalpha but not other IkappaB members is crucial for postrepression activation of NF-kappaB. We propose that this IkappaBalpha-specific function is important for certain physiological and pathological conditions where NF-kappaB needs to be rapidly reactivated.