Written by Miyako Rogers, Science Writer
A new study in Nature is the first to demonstrate the role that the nucleolus plays in regulating RNA turnover of pro-inflammatory genes during infection. This study goes into great detail, investigating mechanisms of action and elucidating the role of nucleolin and the Rrp6-exosome complex in this process. These findings further our understanding of the molecular pathology of inflammation-associated diseases and could help improve therapies for autoimmune diseases, cancer and septic reactions.
The role of nucleolus in RNA decay
The RNA turnover of pro-inflammatory mediators must be tightly controlled during infection or an inflammatory response. Most studies have investigated RNA decay pathways in the nucleus or the cytosol but have never focussed on the nucleolus or studied the process under infectious conditions. The nucleolus is a subnuclear compartment and is well characterized as a site for ribosomal RNA synthesis, but recent research has shown that it has other roles such as transmitting signals in response to genome instability and responding to viral infection.
In this study, researchers report a role of the nucleolus as an essential site of inflammatory pre-mRNA decay. First, researchers observed changes in the morphology of the nucleolus in response to bacterial lipopolysaccharide (LPS) infection and saw that the nucleolus exhibited fused morphology and changed in size over the course of LPS infection. Researchers then extracted fractions from cells infected with LPS and conducted RNA-sequencing. Analysis of RNA-seq data revealed that not only do inflammatory genes have higher intronic read densities than non-inflammatory genes but their mRNAs are highly enriched in nucleoli during infection. As introns are known to increase transcript levels by enhancing transcription, nuclear export and the efficiency of mRNA translation, this suggests that inflammatory genes are highly expressed in nucleoli during infection. The highly enriched inflammatory mRNAs further support this conclusion.
Mechanisms of action
Further investigations in this study revealed that nucleolin (NCL), a protein ubiquitous to the nucleolus, acts as a guide, recruiting inflammatory pre-mRNAs to the nucleolus. NCL does this by recruiting cytosine or uracil-rich sequences containing inflammatory pre-mRNAs and also recruits the Rrp6-exosome complex. Rrp6 binds core exosomes in the nucleus, thus facilitating RNA degradation. In this way, NCL brings together the components necessary for RNA degradation and inflammatory pre-mRNAs together. As a result, NCL depletion causes aberrant hyperinflammation, and cells with low NCL levels had a severe lethal reaction to LPS infection.
This process describes a novel nucleolus-dependent pathway for regulating RNA turnover of inflammatory mediators and thus maintaining immunological homeostasis during infection. These new mechanistic insights highlight the previously unknown role of the nucleolus in the inflammatory response.