A novel IκB protein, IκB-ζ, induced by proinflammatory stimuli, negatively regulates nuclear factor-κB in the nuclei
A novel IκB protein, IκB-ζ, induced by proinflammatory stimuli, negatively regulates nuclear factor-κB in the nuclei
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DOI：
10.1074/jbc.m103426200
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发表时间：
2001-07-20
影响因子：
4.8
通讯作者：
Takeshige, K
中科院分区：
文献类型：
--
作者：
Yamazaki, S;Muta, T;Takeshige, K
转录因子核因子-kappaB(NF-kappaB)在多种细胞功能中发挥重要作用，其活性受胞浆抑制物I-kappaB的严格调控。我们在这里报道了I kappaB蛋白家族的一个新成员，I kappaB-Zeta，在其羧基末端含有6个Ankyrin重复序列。脂多糖刺激后，I kappaB-Zeta基因表达增强。IL-1β刺激也可观察到I kappaB-Zeta的诱导，但肿瘤坏死因子-α不能。与胞浆I kappaB-α、-β和-epsilon不同，诱导的I kappaB-Zeta通过其氨基末端定位于细胞核，与其他蛋白质没有同源性。瞬时表达的I kappaB-Zeta抑制了核转录因子kappaB的活性，但不影响核转录因子kappaB在刺激下的核转位。重组I kappaB-Zeta蛋白抑制p65/p50异源二聚体和p50/p50同源二聚体的DNA结合，因此，I kappaB-Zeta负性调节核因子-kappaB活性，可能是为了防止过度炎症。此外，I kappaB-Zeta基因的转导使细胞对肿瘤坏死因子-α诱导的细胞凋亡更加敏感。I kappaB-Zeta的促凋亡活性进一步表明，它可能是炎症和其他生物相关过程的关键调节因子之一。
The transcription factor nuclear factor-kappaB (NF-kappaB) plays crucial roles in a wide variety of cellular functions and its activity is strictly regulated by cytosolic inhibitors known as I kappa Bs. We here report a new member of the I kappaB protein family, I kappaB-zeta, harboring six ankyrin repeats at its carboxyl terminus. I kappaB-zeta mRNA is strongly induced after stimulation by lipopolysaccharide. The induction of I kappaB-zeta is also observed by stimulation with interleukin-1 beta but not by tumor necrosis factor-alpha. In contrast to cytosolic I kappaB-alpha, -beta, and -epsilon, the induced I kappaB-zeta localizes in the nucleus via its amino-terminal region, which shows no homology with other proteins. Transiently expressed I kappaB-zeta inhibits the NF-kappaB activity without affecting the nuclear translocation of NF-kappaB upon stimulation. The expressed I kappaB-zeta preferentially associates with the NF-kappaB subunit p50 rather than p65 and recombinant I kappaB-zeta proteins inhibit the DNA binding of the p65/p50 heterodimer and the p50/p50 homodimer, Thus, I kappaB-zeta negatively regulates NF-kappaB activity in the nucleus, possibly in order to prevent excessive inflammation. Moreover, transfection of I kappaB-zeta renders cells more susceptible to apoptosis induced by tumor necrosis factor-alpha. The proapoptotic activity of I kappaB-zeta further suggests that it might be one of key regulators for inflammation and other biologically relevant processes.