Identification of a novel, NF-?B nucleolar stress response pathway
Identification of a novel, NF-?B nucleolar stress response pathway
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新型 NF-κB 核仁应激反应途径的鉴定
DOI：
10.1101/100255
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Chen J
核仁是一种多功能细胞器，在维持细胞在应激状态下的动态平衡方面起着关键作用。然而，核仁如何感知压力和协调特定的表型结果，仍然知之甚少。在这里，我们确定了一种新的核仁应激反应途径，最终导致NF-κB的激活。使用多种方法，我们证明了POLI复合体的特定破坏刺激了NF-κB信号传递。与核仁应激的范式不同，这种刺激不是由抑制rRNA转录引起的。我们发现了一种新的机制，通过特定的压力破坏核仁，涉及CDK4的抑制，从而依赖于UBF-p14ARF对Poli复合体成分TIF-IA的降解。我们发现这种非典型的核仁应激反应与独特的核仁结构有关。此外，我们还证明它位于NF-κB信号的上游。最后，我们在人类临床样本中探索了这一途径与阿司匹林反应的相关性，并证明了TIF-IA降解和NF-κB途径激活之间的相关性。总之，这些数据为理解核仁应激反应提供了一个概念性的进步，具有治疗意义。
The nucleolus is a multifunctional organelle that plays a critical role in maintaining cellular homeostasis under stress. However, how nucleoli sense stress and coordinate specific phenotypic outcomes, remains poorly understood. Here, we identify a novel nucleolar stress response pathway that culminates in activation of NF-κB. Using multiple approaches, we show that specific disruption of the PolI complex stimulates NF-κB signalling. Unlike the paradigm of nucleolar stress, this stimulation is not caused by inhibition of rRNA transcription. We identify a novel mechanism by which specific stresses disrupt nucleoli involving CDK4 inhibition and consequently, UBF-p14ARF-dependent degradation of the PolI complex component, TIF-IA. We show this atypical nucleolar stress response is associated with a distinctive nucleolar architecture. Furthermore, we show it lies upstream of NF-κB signalling. Finally, we explore the relevance of this pathway in response to aspirin in human clinical samples and demonstrate a correlation between TIF-IA degradation and NF-κB pathway activation. Together, these data provide a conceptual advance in understanding of nucleolar stress response with therapeutic implications.