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首页> 外文期刊>Cell Research >Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autopha-gy-mediated degradation
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Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autopha-gy-mediated degradation

机译：Hsp90调节涉及保护NF-κB诱导激酶（NIK）免受自噬介导的降解的NF-κB2p100加工

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摘要

NF-κB-inducing kinase (NIK) is required for NF-κB activation based on the processing of NF-κB2 p100. Here we report a novel mechanism of NIK regulation involving the chaperone 90 kDa heat shock protein (Hsp90) and autophagy. Functional inhibition of Hsp90 by the anti-tumor agent geldanamycin (GA) efficiently disrupts its interaction with NIK, resulting in NIK degradation and subsequent blockage of p100 processing. Surprisingly, GA-induced NIK degradation is mediated by autophagy, but largely independent of the ubiquitin-proteasome system. Hsp90 seems to be specifically involved in the folding/stabilization of NIK protein, because GA inhibition does not affect NIK mRNA transcription and translation. Furthermore, Hsp90 is not required for NIK-mediated recruitment of the a subunit of IκB kinase to p100, a key step in induction of p100 processing. These findings define an alternative mechanism for Hsp90 client degradation and identify a novel function of autophagy in NF-κB regulation. These findings also suggest a new therapeutic strategy for diseases associated with p100 processing.
机译：基于NF-κB2p100的加工，NF-κB激活需要NF-κB诱导激酶（NIK）。在这里，我们报告了涉及伴侣蛋白90 kDa热激蛋白（Hsp90）和自噬的NIK调节的新机制。抗肿瘤药格尔德霉素（GA）对Hsp90的功能性抑制可有效破坏其与NIK的相互作用，从而导致NIK降解并随后阻止p100加工。出人意料的是，GA诱导的NIK降解是由自噬介导的，但在很大程度上与泛素-蛋白酶体系统无关。 Hsp90似乎特别参与了NIK蛋白的折叠/稳定化，因为GA抑制作用不会影响NIK mRNA的转录和翻译。此外，NIK介导的IκB激酶亚基募集至p100不需要Hsp90，这是诱导p100加工的关键步骤。这些发现为Hsp90客户降解定义了另一种机制，并确定了自噬在NF-κB调节中的新功能。这些发现还提出了与p100加工相关的疾病的新治疗策略。

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