PT - JOURNAL ARTICLE AU - Jingyu Chen AU - Ian T Lobb AU - Pierre Morin AU - Sonia M Novo AU - James Simpson AU - Kathrin Kennerknecht AU - Fiona Oakley AU - Lesley A. Stark TI - Activation of NF-κB by a novel, CDK4-regulated, nucleolar stress response pathway AID - 10.1101/100255 DP - 2017 Jan 01 TA - bioRxiv PG - 100255 4099 - http://biorxiv.org/content/early/2017/01/13/100255.short 4100 - http://biorxiv.org/content/early/2017/01/13/100255.full AB - 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.