![]() Besides, many viruses can employ the nucleolus or nucleolar proteins to promote different steps of their life cycle such as replication, transcription and assembly. Nucleoli are membrane-less structures located within the nucleus and are known to be involved in many cellular functions, including stress response and cell cycle regulation. In addition, the chapter will also provide a brief outline of noncanonical subcellular locations and of other unconventional functions attributed to miRNAs, both suggesting that we have only begun to touch upon the complexity and versatility of the regulatory functions exerted by these short noncoding RNAs. Specific paragraphs will cover the biology of the main innate RNA sensors, ex-miRNA biogenesis, uptake by recipient cells and delivery to innate receptors, as well as experimental evidence of ex-miRNAs regulating the pathogenesis of inflammation-dependent diseases via stimulation of RNA sensors. The main focus of this chapter is to convey a comprehensive view of ex-miRNAs as ligands of innate immune receptors. In this scenario, ex-miRNAs would regulate the responses of neighboring cells by inducing cytokine secretion which, in turn, would trigger “sterile” inflammation and immune activation. In addition, we and others have proposed another regulatory function of EV-miRNAs, namely, the triggering of innate immune receptors. Indeed, ample experimental evidence demonstrates that EV-miRNAs penetrate into target cells, where they exert posttranscriptional regulation of specific target messenger RNAs. ![]() However, the fact that cells can also operate specific sorting of secreted miRNAs, suggested that ex-miRNAs may work as soluble messengers regulating cell-to-cell communications. ![]() Ex-miRNAs can be released upon cell damage or death, so possibly representing remnants devoid of any particular function. This largely depends on their association with proteins protecting them from degradation, such as those of the AGO family, and/or on their loading into extracellular vesicles (EV-miRNAs) and apoptotic bodies. Ex-miRNAs are remarkably stable in harsh conditions, including high nuclease concentrations and extreme pH variations. The existence of extracellular miRNAs (ex-miRNAs) was first described in plasma and soon demonstrated in virtually all biological fluids. Refer to text for detailed explanations of these pathways and for references. The outcomes of increases p53 are summarized in (D), namely the upregulation of p53 target genes which ultimately leads to either cell-cycle arrest or apoptosis, and the inhibition of ribosome biogenesis via the inhibition of rRNA transcription. Grayscale text and objects indicate processes that occur during normal physiological conditions, whereas orange text and objects show the changes that occur following stress that result in increased p53 levels and activity. The size of each quadrant represents their relative importance according to current literature. The different mechanisms have been separated into three broad categories, namely those that primarily involve either (A) alterations of protein-protein interactions, (B) changes to the translational profile, or (C) prevention of coribosomal export of p53 and Hdmd2. Overview of the Nucleolar-Related, Stress-Induced Mechanisms that Result in Increased p53 Activity In contrast, DRB treatment induces nucleolar fragmentation and unravelling of the FC, as well as CB disruption and association of coilin with the nucleolus in cap-like structures. UV-C treatment induces nucleolar segregation and relocalization of coilin to nucleoplasmic microfoci. All images show UBF (nucleolar fibrillar center) in red and coilin (CB) in green. (Right panel) DRB-treated cells (3 hr, 25 μg/mL). (Middle panel) UV-C-treated cells (6 hr postirradiation, 30 J/m2). (C) Examples of stress-induced changes in nucleolar and CB organization in U2OS cells. FC is visualized using antibodies against UBF, DFC using antibodies against Nop58, and GC using antibodies against B23/NPM. (B) Fluorescence microscopy images showing the three subnucleolar compartments in human U2OS cells. ![]() Schematic representation of nucleolar tripartite internal organization, formed by the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC) (right panel). (A) Differential interference contrast (DIC) image of live HeLa cells: nucleoli are readily observed as phase-dense structures. Overview of Nucleolar Organization under Physiological Conditions in the Mammalian Cell Nucleus, and Visualization by Immunofluorescence of Stress-Induced Changes to Nucleolar and Cajal Body Organization
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