Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation.
Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation.
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DOI：
10.1126/scisignal.2000778
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发表时间：
2010-05-25
影响因子：
7.3
通讯作者：
Cheng G
中科院分区：
文献类型：
--
作者：
Razani B;Zarnegar B;Ytterberg AJ;Shiba T;Dempsey PW;Ware CF;Loo JA;Cheng G
典型和非典型核因子κB （NF-κB）信号是负责NF-κB二聚体从其抑制剂中释放的两个基本途径。NF-κB信号增强导致炎症和增生性疾病；因此，限制其活性的抑制途径至关重要。尽管多种负反馈机制控制着典型NF-κB信号，但尚未发现非典型途径的负反馈机制。本研究描述了非典型NF-κB信号的负反馈控制机制，该机制减弱了NF-κB诱导激酶（NIK）的稳定性，NIK是由B细胞活化因子受体（BAFF-R）和淋巴毒素β受体（LTβR）诱导的非典型途径的中心调节激酶。先前认为，在非典型NF-κB通路中，κB激酶α (IKKα)抑制剂位于NIK的下游；我们发现IKKα对NIK的磷酸化会破坏NIK的稳定性。在没有ikk α介导的负反馈的情况下，受体结扎后NIK的丰度增加。一种ikk α靶向丝氨酸残基突变的NIK比野生型NIK更稳定，并导致非典型NF-κB信号传导增加。因此，除了通过包含肿瘤坏死因子受体相关因子（TRAF）和细胞凋亡抑制剂（cIAP）蛋白的复合物调节未受刺激细胞中NIK的基础丰度外，ikk α依赖性NIK的不稳定阻止了受体连接后非典型NF-κB途径的不受控制的活性。
Canonical and noncanonical nuclear factor κB (NF-κB) signaling are the two basic pathways responsible for the release of NF-κB dimers from their inhibitors. Enhanced NF-κB signaling leads to inflammatory and proliferative diseases; thus, inhibitory pathways that limit its activity are critical. Whereas multiple negative feedback mechanisms control canonical NF-κB signaling, none has been identified for the noncanonical pathway. Here, we describe a mechanism of negative feedback control of noncanonical NF-κB signaling that attenuated the stabilization of NF-κB–inducing kinase (NIK), the central regulatory kinase of the non-canonical pathway, induced by B cell–activating factor receptor (BAFF-R) and lymphotoxin β receptor (LTβR). Inhibitor of κB (IκB) kinase α (IKKα) was previously thought to lie downstream of NIK in the non-canonical NF-κB pathway; we showed that phosphorylation of NIK by IKKα destabilized NIK. In the absence of IKKα-mediated negative feedback, the abundance of NIK increased after receptor ligation. A form of NIK with mutations in the IKKα-targeted serine residues was more stable than wild-type NIK and resulted in increased noncanonical NF-κB signaling. Thus, in addition to the regulation of the basal abundance of NIK in unstimulated cells by a complex containing tumor necrosis factor receptor–associated factor (TRAF) and cellular inhibitor of apoptosis (cIAP) proteins, IKKα-dependent destabilization of NIK prevents the uncontrolled activity of the noncanonical NF-κB pathway after receptor ligation.
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DOI：
10.1073/pnas.0805186105
发表时间：
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影响因子：
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作者：
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通讯作者：
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作者：
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