Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription
Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription
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DOI：
10.1093/emboj/19.18.4976
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发表时间：
2000-09-15
期刊：
影响因子：
11.4
通讯作者：
Yeh, WC
中科院分区：
文献类型：
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作者：
Bonnard, M;Mirtsos, C;Yeh, WC
肿瘤坏死因子受体相关因子2(TRAF2)在肿瘤坏死因子α(TNFα)等细胞因子的作用下，对核转录因子kappaB的激活起重要作用。在这项研究中，我们纯化并鉴定了一种新的激酶(T2K，也称为TBK1或NAK)，它与TRAF2结合，并在体外显示出对I-kappa Bα的激酶活性。用T2K基因缺陷小鼠研究T2K的生理功能。杂合子看起来正常，但T2K(-/-)动物死于与E14.5相似的大量肝脏变性和凋亡，然而，来自T2K缺陷胎肝的造血祖细胞支持正常的淋巴细胞发育。此外，T2K(-/-)胚胎成纤维细胞和胸腺细胞对肿瘤坏死因子α诱导的细胞凋亡没有表现出更高的敏感性。T2K(-/-)胚胎成纤维细胞在肿瘤坏死因子α或白介素1诱导下，表现出I-kappa B和kappa B结合活性的正常降解。然而，核因子-kappa B引导的转录显著减少。这些结果表明，与I-kappa B激酶β和NF-kappa B的REIA亚基一样，T2K在保护胚胎肝脏免受细胞凋亡中起着关键作用，然而，T2K在激活NF-kappa B介导的转录中具有独特的作用，显然不依赖于I-kappa B的降解和NF-kappa B的DNA结合。
induction of NF-kappa B-dependent transcription requires phosphorylation and subsequent degradation of I-kappa B, an inhibitor of NF-kappa B, followed by nuclear translocation and DNA binding of NF-kappa B. Tumor necrosis factor receptor-associated factor 2 (TRAF2) plays a role in NF-kappa B activation in response to cytokines such as tumor necrosis factor alpha (TNF alpha). In this study, we purified and characterized a novel kinase (T2K, also known as TBK1 or NAK), which associates with TRAF2 and exhibits kinase activity towards I-kappa B alpha in vitro. The physiological function of T2K was investigated using T2K-deficient mice. Heterozygotes appear normal, but t2k(-/-) animals die at similar to E14.5 of massive liver degeneration and apoptosis, Nevertheless, hematopoietic progenitors from T2K-deficient fetal liver support normal lymphocyte development. Furthermore, t2k(-/-) embryonic fibroblasts and thymocytes do not display increased sensitivity to TNF alpha-induced apoptosis. In response to either TNF alpha or IL-1, induction, t2k(-/-) embryonic fibroblasts exhibit normal degradation of I-kappa B and kappa B-binding activity. However, NF-kappa B-directed transcription is dramatically reduced. These results demonstrate that, like I-kappa B kinase beta and the ReIA subunit of NF-kappa B, T2K is critical in protecting embryonic liver from apoptosis, However, T2K has a unique role in the activation of NF-kappa B-directed transcription, apparently independent of I-kappa B degradation and NF-kappa B DNA binding.