The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis.
The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis.
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DOI：
10.1084/jem.189.11.1839
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发表时间：
1999-06-07
期刊：
影响因子：
--
通讯作者：
Karin M
中科院分区：
文献类型：
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作者：
Li ZW;Chu W;Hu Y;Delhase M;Deerinck T;Ellisman M;Johnson R;Karin M
IκB激酶（IKK）复合体由IKKα、IKKβ和IKKγ (NEMO)三个亚基组成。虽然IKKα和IKKβ是高度相似的催化亚基，都能在体外磷酸化i - κ b，但IKKγ是一个调控亚基。先前的生化和遗传学分析表明，尽管IKKα和IKKβ具有相似的结构和体外激酶活性，但它们具有不同的功能。令人惊讶的是，IKK α位点的破坏并没有消除促炎刺激对IKK的激活，只导致核因子(NF)-κB激活的小幅下降。现在我们描述Ikkβ位点破坏的病理生理后果。ikk β缺乏的小鼠在妊娠中期死于不受控制的肝脏凋亡，这种表型与NF-κB的RelA （p65）和NF-κB1 （p50/p105）亚基缺乏的小鼠非常相似。因此，IKKβ缺陷细胞在响应肿瘤坏死因子α或白细胞介素1时，IKK和NF-κB的激活存在缺陷。由此可见，IKKβ而非IKKα在IKK激活和NF-κB活性诱导中起主要作用。在缺乏IKKβ的情况下，IKKα对IKK激活剂无反应。
The IκB kinase (IKK) complex is composed of three subunits, IKKα, IKKβ, and IKKγ (NEMO). While IKKα and IKKβ are highly similar catalytic subunits, both capable of IκB phosphorylation in vitro, IKKγ is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKα and IKKβ have distinct functions. Surprisingly, disruption of the Ikkα locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-κB activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-κB1 (p50/p105) subunits of NF-κB. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-κB in response to either tumor necrosis factor α or interleukin 1. Thus IKKβ, but not IKKα, plays the major role in IKK activation and induction of NF-κB activity. In the absence of IKKβ, IKKα is unresponsive to IKK activators.