Crosstalk between NF-κB and Nucleoli in the Regulation of Cellular Homeostasis

Abstract

Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence, and apoptosis. NF-κB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. While nucleolar and NF-κB pathways are distinct, it is increasingly apparent that they converge at multiple levels. Exposure of cells to certain insults causes a specific type of nucleolar stress that is characterised by degradation of the PolI complex component, TIF-IA, and increased nucleolar size. Recent studies have shown that this atypical nucleolar stress lies upstream of cytosolic IκB degradation and NF-κB nuclear translocation. Under these stress conditions, the RelA component of NF-κB accumulates within functionally altered nucleoli to trigger a nucleophosmin dependent, apoptotic pathway. In this review, we will discuss these points of crosstalk and their relevance to anti-tumour mechanism of aspirin and small molecule CDK4 inhibitors. We will also briefly the discuss how crosstalk between nucleoli and NF-κB signalling may be more broadly relevant to the regulation of cellular homeostasis and how it may be exploited for therapeutic purpose.

Keywords: CDK4; I-kappaB; NF-κB; Nucleolus; RelA; TIF-IA(RRN3); aspirin; cancer; neurodegenerative disorders; non-steroidal anti-inflammatory drugs (NSAIDs); p65; stress.

Figure 1

Top: TIF-IA is targeted by multiple kinase and phosphatase pathways. Bottom: the phosphorylation status controls the transcriptional activity of the pre-initiation complex, of which TIF-IA is a vital component. NES-nuclear export signal. NLS-nuclear localisation signal. Insert; confocal image showing the localisation of GFP-TIF-IA in fibrillar centres (FC) of nucleoli and cherry-fibrillarin in the surrounding dense fibrillar component (DFC) in fixed colorectal cancer cells. DAPI marks the DNA.

Figure 2

Nucleoli play a critical role in maintaining cellular homeostasis. Nucleolar function is altered in response to a plethora of cytotoxic and environmental stresses. This disruption modulates an array of cellular processes which allow cells to recover or, if the damage is to great, to undergo cell death.

Figure 3

TIF-IA-NF-kB-nucleololar stress response. When cells are exposed to a variety of specific stresses, ceramide is generated leading to inhibition of CDK4. This inhibition induces degradation of TIF-IA (in a manner dependent upon UBF and p14ARF), which in turn causes increased nucleolar size, gross changes in nucleolar morphology and degradation of IkB. IkB degradation allows RelA/NF-kB to translocate into the nucleus and recruit a COMMD1 dependent ubiquitin ligase complex. Ubiquitination of RelA by this specific complex targets the protein to nucleoli, where it binds nucleophosmin (NPM), causing this protein to relocate out of nucleoli to the cytoplasm, where it is free to bind BAX and transport BAX to the mitochondria to mediate apoptosis. The signalling network(s) that links altered nucleolar function to IkB degradation is unknown. Inset: Immunomicrograph showing enlarged segregated nucleoli and nucleolar accumulation of RelA in response to aspirin (5mM, 16h). DAPI depicts DNA.