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 insultinduced 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.

A memory of RPS25 loss drives resistance phenotypes

“…RPs do much more than chaperone rRNA maturation concordant with their assembly, and several biogenesis checkpoints exist, providing opportunities for feedback loops to sense proper assembly (Klinge and Woolford, 2019;Peña et al, 2017). The complexity of ribosome biogenesis in eukaryotes is amplified by the existence of the nucleolus-a subnuclear, membraneless organelle that is a key hub for stress sensing (Boulon et al, 2010;Yang et al, 2018). Our RNA-seq analysis highlighted the dysregulation of the nucleolus in the RPS25 KO, and our quantification of the subnuclear intensity of DDX21 supports this assessment (Figure 6 and Figure 6-FigS1-2).…”

“…If genetic mutations in RPs drive reorganization of nuclear architecture during development, rather than directly interfering with translation, gene therapy-mediated repair of such mutations in somatic cells might ultimately fail. Furthermore, the therapeutic reduction of nucleolar RPs like RPS25 may cause disease if they drive dysregulation of the nucleolus (Boulon et al, 2010;Kampen et al, 2019;Yang et al, 2018).…”

Tick-borne encephalitis virus inhibits rRNA synthesis and host protein production in human cells of neural origin

“…Tick-borne encephalitis virus and host rRNA/protein shut-off Previously, a link between the inhibition of expression of 45-47S pre-rRNA and nucleolar stress was documented [31]. There are several hallmarks typical for nucleolar stress including disruption of nucleolus structure [51]. We, therefore, characterised the localization and production of nascent RNA at the cellular level and also investigated the structure of the nucleolus.…”

Nucleolar stress inDrosophilaneuroblasts, a model for human ribosomopathies

“…Ribosome biogenesis requires high energy expenditures by the cell; approximately 60% of total cellular transcription is devoted to rRNA, with some 2000 ribosomes assembled per minute in actively growing yeast cells (Warner 1999; Woolford and Baserga, 2013). Any perturbation in ribosome biogenesis disrupts cell homeostasis; this is now called nucleolar (or ribosome) stress (Golomb et al, 2014; Tsai and Pederson, 2014; Yang et al, 2018). In humans, nucleolar stress due to mutations in ribosome biogenesis factors (RBFs), processing snoRNPs, or the ribosomal proteins themselves results in disease states collectively called ribosomopathies, of which there are several (Narla and Ebert, 2010).…”