二聚体转录因子(TF)的核因子κB(NF-κB)家族成员调节涉及免疫应答,炎症,细胞存活和癌症的大量基因的表达。NF-κBTFs响应各种刺激(包括细胞因子,感染因子和辐射诱导的DNA双链断裂)而被快速激活。在未刺激的细胞中,某些NF-κBTFs与抑制性IκB蛋白结合,从而被隔离在细胞质中。激活导致IκB蛋白磷酸化,随后被泛素化酶识别。导致的IκB蛋白的蛋白酶体降解释放了与IκB结合的NF-κBTF,这些TFs易位至细胞核以驱动靶基因的表达。两种具有高度序列相似性的蛋白激酶IKKα和IKKβ,介导IκB蛋白的磷酸化,并代表导致NF-κB活化的大多数信号转导途径的汇合点。细胞中的大多数IKKα和IKKβ分子是IKK复合物的一部分,该复合物还包含称为IKKγ或NEMO的调节亚基。尽管有广泛的序列相似性,但由于它们的底物特异性和调控方式不同,IKKα和IKKβ仍具有截然不同的功能。IKKβ(和IKKγ)对于促炎性信号传导级联(例如由肿瘤坏死因子α(TNFα)或脂多糖(LPS)触发的级联反应)对NF-κB的快速激活至关重要。相反,IKKα在特定形式的NF-κB的激活中起一定作用,以响应TNF家族成员的子集,并且还可以减弱IKKβ驱动的NF-κB的激活。此外,IKKα参与角质形成细胞的分化,但是该功能与其激酶活性无关。几年前,鉴定出两种蛋白激酶,它们分别表现为IKKε或IKK-i和一种分别命名为TBK1(TANK结合激酶),NAK(NF-κB激活激酶)或T2K(TRAF2相关激酶)。与IKKα和IKKβ的结构相似性。这些蛋白激酶对于干扰素应答因子3(IRF3)和IRF7,TF在I型干扰素(IFN-I)诱导中起关键作用的激活很重要。IKK和IKK相关激酶共同作用于激活宿主防御系统。这篇综述着重于IKK和IKK相关激酶的功能以及调节其活性的分子机制。鉴定出一种与IKKα和IKKβ在结构上相似的化合物,一种称为IKKε或IKK-i,另一种称为TBK1(TANK结合激酶),NAK(NF-κB激活激酶)或T2K(TRAF2相关激酶)。这些蛋白激酶对于干扰素应答因子3(IRF3)和IRF7,TF在I型干扰素(IFN-I)诱导中起关键作用的激活很重要。IKK和IKK相关激酶共同作用于激活宿主防御系统。这篇综述着重于IKK和IKK相关激酶的功能以及调节其活性的分子机制。鉴定出一种与IKKα和IKKβ在结构上相似的化合物,一种称为IKKε或IKK-i,另一种称为TBK1(TANK结合激酶),NAK(NF-κB活化激酶)或T2K(TRAF2相关激酶)。这些蛋白激酶对于干扰素应答因子3(IRF3)和IRF7,TF在I型干扰素(IFN-I)诱导中起关键作用的激活很重要。IKK和IKK相关激酶共同作用于激活宿主防御系统。这篇综述着重于IKK和IKK相关激酶的功能以及调节其活性的分子机制。这些蛋白激酶对于干扰素应答因子3(IRF3)和IRF7,TF在I型干扰素(IFN-I)诱导中起关键作用的激活很重要。IKK和IKK相关激酶共同作用于激活宿主防御系统。这篇综述着重于IKK和IKK相关激酶的功能以及调节其活性的分子机制。这些蛋白激酶对于干扰素应答因子3(IRF3)和IRF7,TF在I型干扰素(IFN-I)诱导中起关键作用的激活很重要。IKK和IKK相关激酶共同作用于激活宿主防御系统。这篇综述着重于IKK和IKK相关激酶的功能以及调节其活性的分子机制。
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Regulation and Function of IKK and IKK-Related Kinases
Members of the nuclear factor kappa B (NF-κB) family of dimeric transcription factors (TFs) regulate expression of a large number of genes involved in immune responses, inflammation, cell survival, and cancer. NF-κB TFs are rapidly activated in response to various stimuli, including cytokines, infectious agents, and radiation-induced DNA double-strand breaks. In nonstimulated cells, some NF-κB TFs are bound to inhibitory IκB proteins and are thereby sequestered in the cytoplasm. Activation leads to phosphorylation of IκB proteins and their subsequent recognition by ubiquitinating enzymes. The resulting proteasomal degradation of IκB proteins liberates IκB-bound NF-κB TFs, which translocate to the nucleus to drive expression of target genes. Two protein kinases with a high degree of sequence similarity, IKKα and IKKβ, mediate phosphorylation of IκB proteins and represent a convergence point for most signal transduction pathways leading to NF-κB activation. Most of the IKKα and IKKβ molecules in the cell are part of IKK complexes that also contain a regulatory subunit called IKKγ or NEMO. Despite extensive sequence similarity, IKKα and IKKβ have largely distinct functions, due to their different substrate specificities and modes of regulation. IKKβ (and IKKγ) are essential for rapid NF-κB activation by proinflammatory signaling cascades, such as those triggered by tumor necrosis factor α (TNFα) or lipopolysaccharide (LPS). In contrast, IKKα functions in the activation of a specific form of NF-κB in response to a subset of TNF family members and may also serve to attenuate IKKβ-driven NF-κB activation. Moreover, IKKα is involved in keratinocyte differentiation, but this function is independent of its kinase activity. Several years ago, two protein kinases, one called IKKε or IKK-i and one variously named TBK1 (TANK-binding kinase), NAK (NF-κB–activated kinase), or T2K (TRAF2-associated kinase), were identified that exhibit structural similarity to IKKα and IKKβ. These protein kinases are important for the activation of interferon response factor 3 (IRF3) and IRF7, TFs that play key roles in the induction of type I interferon (IFN-I). Together, the IKKs and IKK-related kinases are instrumental for activation of the host defense system. This Review focuses on the functions of IKK and IKK-related kinases and the molecular mechanisms that regulate their activities.