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首页> 外文期刊>Molecular and Cellular Biology >Shared Pathways of IκB Kinase-Induced SCFβTrCP-Mediated Ubiquitination and Degradation for the NF-κB Precursor p105 and IκBα
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Shared Pathways of IκB Kinase-Induced SCFβTrCP-Mediated Ubiquitination and Degradation for the NF-κB Precursor p105 and IκBα

机译：IκB激酶诱导的SCFβTrCP介导的泛素化和NF-κB前体p105和IκBα降解的共同途径

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p105 (NFKB1) acts in a dual way as a cytoplasmic IκB molecule and as the source of the NF-κB p50 subunit upon processing. p105 can form various heterodimers with other NF-κB subunits, including its own processing product, p50, and these complexes are signal responsive. Signaling through the IκB kinase (IKK) complex invokes p105 degradation and p50 homodimer formation, involving p105 phosphorylation at a C-terminal destruction box. We show here that IKKβ phosphorylation of p105 is direct and does not require kinases downstream of IKK. p105 contains an IKK docking site located in a death domain, which is separate from the substrate site. The substrate residues were identified as serines 923 and 927, the latter of which was previously assumed to be a threonine. S927 is part of a conserved DSGΨ motif and is functionally most critical. The region containing both serines is homologous to the N-terminal destruction box of IκBα, -β, and -?. Upon phosphorylation by IKK, p105 attracts the SCF E3 ubiquitin ligase substrate recognition molecules βTrCP1 and βTrCP2, resulting in polyubiquitination and complete degradation by the proteasome. However, processing of p105 is independent of IKK signaling. In line with this and as a physiologically relevant model, lipopolysaccharide (LPS) induced degradation of endogenous p105 and p50 homodimer formation, but not processing in pre-B cells. In mutant pre-B cells lacking IKKγ, processing was unaffected, but LPS-induced p105 degradation was abolished. Thus, a functional endogenous IKK complex is required for signal-induced p105 degradation but not for processing.
机译：p105（NFKB1）在细胞质中以双重方式充当细胞质IκB分子和NF-κBp50亚基的来源。 p105可以与其他NF-κB亚基形成各种异二聚体，包括其自身的加工产物p50，并且这些复合物具有信号响应性。通过IκB激酶（IKK）复合物发出的信号会引起p105降解和p50同型二聚体形成，涉及在C末端破坏盒处p105磷酸化。我们在这里显示p105的IKKβ磷酸化是直接的，不需要IKK下游的激酶。 p105包含一个位于死亡区域的IKK对接位点，与底物位点分开。底物残基被鉴定为丝氨酸923和927，先前假定后者为苏氨酸。 S927是保守的DSGα基序的一部分，在功能上最为关键。包含两个丝氨酸的区域与IκBα，-β和-α的N末端破坏盒同源。通过IKK磷酸化后，p105会吸引SCF E3泛素连接酶底物识别分子βTrCP1和βTrCP2，从而导致多泛素化并被蛋白酶体完全降解。但是，p105的处理与IKK信号无关。与此相符并且作为生理学相关的模型，脂多糖（LPS）诱导了内源性p105和p50同型二聚体形成的降解，但未在pre-B细胞中加工。在缺乏IKKγ的突变pre-B细胞中，加工过程不受影响，但LPS诱导的p105降解被取消。因此，信号诱导的p105降解需要功能性内源性IKK复合物，而加工则不需要。

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