Members of the nuclear factor kappa B (NF-κB) family of dimeric transcription factors (TF) regulate the expression of a large number of genes involved in immune response, inflammation, cell survival, and cancer. The two protein kinases IKKα and IKKβ, which have a high degree of sequence similarity, mediate the phosphorylation of IκB proteins and represent the confluence of most signal transduction pathways that lead to NF-κB activation. Most IKKα and IKKβ molecules in cells are part of the IKK complex, which also contains regulatory subunits called IKKγ or NEMO. Despite extensive sequence similarities, IKKα and IKKβ still have distinct functions due to their different substrate specificities and regulatory approaches. IKKβ (and IKKγ) are essential for the rapid activation of NF-κB by pro-inflammatory signaling cascades (such as those triggered by tumor necrosis factor alpha (TNFα) or lipopolysaccharide (LPS)). In contrast, IKKα plays a role in the activation of specific forms of NF-κB in response to a subset of TNF family members and can also attenuate IKKβ-driven activation of NF-κB. In addition, IKKα is involved in the differentiation of keratinocytes, but this function is not related to its kinase activity. A few years ago, two protein kinases were identified, which manifested as IKKε or IKK-i and one named TBK1 (TANK-binding kinase), NAK (NF-κB activating kinase), or T2K (TRAF2-related kinase), respectively. Structural similarity to IKKα and IKKβ. These protein kinases are important for the activation of interferon response factor 3 (IRF3) and IRF7, TF, which play a key role in the induction of type I interferon (IFN-I). IKK and IKK-related kinases work together to activate host defense system.
IKKγ is ubiquitinated in response to DSB after it is sulfonylated, and its lysine residue may be the same as the lysine residue used for SUMO attachment. A polyubiquitin chain was used instead of SUMO with IKKγ attached. Therefore, it has been proposed that IKOγ is placed next to nuclear ATM depending on the nuclear translocation of SUMO, which is activated by DSB to phosphorylate IKKγ, triggering its ubiquitination and nuclear export, which ultimately leads to modified IKKγ and IKKα and IKKβ-binding activation. Many aspects of this model have yet to be identified and characterized: ATM phosphorylation sites in IKKγ need to be mapped, and ubiquitinase remains to be identified and characterized. In addition, a nuclear export mechanism that seems to rely on ubiquitination and vetoes nuclear positioning by SUMO needs to be identified. It is also important to observe whether the ubiquitination of IKKγ is sufficient to activate IKK, or whether ubiquitination is only required for nuclear export. DSB-mediated NF-κB activation also depends on RIP1. In this case, autocrine TNFα-dependent NF-κB activation was ruled out. In addition, the induction of DSB with adriamycin induced the interaction of RIP1 with IKKγ, which depends on ATM activity, suggesting that RIP1 functions downstream of ATM. Like TNFR1 signaling, RIP1 kinase activity is essential for DSB-mediated NFκB activation. IKKγ's ubiquitination may control its interaction with RIP1, which may be a scaffolding protein that eventually leads to IKK activation. Several aspects of the model are speculative and the exact mode of interaction between RIP1 and IKKγ needs to be studied and its relationship to IKK activation.
As mentioned above, IKK activation is likely to involve trans autophosphorylation of its catalytic subunits IKKα and IKKβ (Figure 1). However, other molecular mechanisms have been proposed to regulate this triggering event. However, the molecular details of IKK activation are unknown. Generally, three mechanisms can be envisaged: (i) direct phosphorylation of one of the IKK catalytic subunits on the activation loop; (ii) IKK polymerisation, resulting in trans autophosphorylation; (iii) through post-translational modification rather than phosphoric acid or conformational changes induced by protein-protein interactions. These mechanisms are not mutually exclusive. For example, phosphorylation at the activation loop of IKKα or IKKβ can be caused by an upstream kinase (IKK-K), or can be attributed to autophosphorylation through the induced proximity of the IKKα-IKKβ dimer. The latter can be mediated by interaction with multimeric receptors or docking proteins, or can be induced by posttranslational modification of IKKγ. We will discuss different mechanisms related to IKK activation.
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