RT Journal Article
SR Electronic
T1 Activation of NF-κB by a novel, CDK4-regulated, nucleolar stress response pathway
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 100255
DO 10.1101/100255
A1 Jingyu Chen
A1 Ian T Lobb
A1 Pierre Morin
A1 Sonia M Novo
A1 James Simpson
A1 Kathrin Kennerknecht
A1 Fiona Oakley
A1 Lesley A. Stark
YR 2017
UL http://biorxiv.org/content/early/2017/01/13/100255.abstract
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.