Nucleolar Stress: hallmarks, sensing mechanism and diseases

Abstract

The nucleolus is a prominent subnuclear compartment, where ribosome biosynthesis takes place. Recently, the nucleolus has gained attention for its novel role in the regulation of cellular stress. Nucleolar stress is emerging as a new concept, which is characterized by diverse cellular insult-induced abnormalities in nucleolar structure and function, ultimately leading to activation of p53 or other stress signaling pathways and alterations in cell behavior. Despite a number of comprehensive reviews on this concept, straightforward and clear-cut way criteria for a nucleolar stress state, regarding the factors that elicit this state, the morphological and functional alterations as well as the rationale for p53 activation are still missing. Based on literature of the past two decades, we herein summarize the evolution of the concept and provide hallmarks of nucleolar stress. Along with updated information and thorough discussion of existing confusions in the field, we pay particular attention to the current understanding of the sensing mechanisms, i.e., how stress is integrated by p53. In addition, we propose our own emphasis regarding the role of nucleolar protein NPM1 in the hallmarks of nucleolar stress and sensing mechanisms. Finally, the links of nucleolar stress to human diseases are briefly and selectively introduced.

Keywords: MDM2; NPM1; nucleolar stress; p53; ribosomal proteins; ribosome biogenesis; translocation.

Figure 1. FIGURE 1: Schematic illustration of nucleolar stress.

Various stressors induce nucleolar stress, accompanied by morphological changes and functional defects, ultimately resulting in activation of p53 signaling pathway and altered cell behavior.

Figure 2. FIGURE 2: Stressors eliciting nucleolar stress.

Two categories of nucleolar stress inducers are direct ribotoxic insults and a wide range of cellular insults.

Figure 3. FIGURE 3: NPM1 translocation under nucleolar stress.

Representative images of NPM1 translocation in HeLa cells under various nucleolar stresses, including H₂O₂ (500 (M, 30 min), hypoxia (1% O₂, 1 h), UV irradiation (100 J m^-2), heat-shock (42°C, 30 min), EBSS starvation (6 h) and Act.D (8 nM, 1 h), examined by immunofluorescence with anti-NPM1 antibody. Bar, 5 (m. Image from ref

Figure 4. FIGURE 4: NPM1 sensing for nucleolar stress.

Nucleolar oxidation is a general response to nucleolar stress. S-glutathionylation and nucleoplasmic translocation of NPM1 are indispensable for p53 activation in nucleolar stress .