Review
RNA decay machines: The exosome

https://doi.org/10.1016/j.bbagrm.2013.01.006Get rights and content

Abstract

The multisubunit RNA exosome complex is a major ribonuclease of eukaryotic cells that participates in the processing, quality control and degradation of virtually all classes of RNA in Eukaryota. All this is achieved by about a dozen proteins with only three ribonuclease activities between them. At first glance, the versatility of the pathways involving the exosome and the sheer multitude of its substrates are astounding. However, after fifteen years of research we have some understanding of how exosome activity is controlled and applied inside the cell. The catalytic properties of the eukaryotic exosome are fairly well described and attention is now drawn to how the interplay between these activities impacts cell physiology. Also, it has become evident that exosome function relies on many auxiliary factors, which are intensely studied themselves. In this way, the focus of exosome research is slowly leaving the test tube and moving back into the cell.

The exosome also has an interesting evolutionary history, which is evident within the eukaryotic lineage but only fully appreciated when considering similar protein complexes found in Bacteria and Archaea. Thus, while we keep this review focused on the most comprehensively described yeast and human exosomes, we shall point out similarities or dissimilarities to prokaryotic complexes and proteins where appropriate.

The article is divided into three parts. In Part One we describe how the exosome is built and how it manifests in cells of different organisms. In Part Two we detail the enzymatic properties of the exosome, especially recent data obtained for holocomplexes. Finally, Part Three presents an overview of the RNA metabolism pathways that involve the exosome. This article is part of a Special Issue entitled: RNA Decay mechanisms.

Highlights

► The eukaryotic exosome is a major ribonuclease for RNA decay and processing. ► The repertoire of catalytic subunits varies among Eukaryota. ► Some catalytic subunits are compartment-specific and give rise to exosome isoforms. ► Substrate threading modulates ribonuclease activities in the holocomplex. ► The many cellular functions of the exosome are mediated by auxiliary factors.

Section snippets

Part One: exosome structure

The eukaryotic exosome is composed of ten to eleven subunits, which can be divided into two major groups with regard to their structural and functional contributions. The first group encompasses nine proteins that form the ‘exosome core’. They are all rather small polypeptides with molecular masses of 20–50 kDa. Three of these are built entirely of RNA binding domains and motifs, whereas the remaining six are single-domain proteins homologous to RNase PH, a homomultimeric enzyme found in

Part two: catalytic properties and mechanisms of the exosome

Despite their structural similarity, the catalytic properties of the eukaryotic exosome core and the prokaryotic exosome core-like complexes are very different. While the latter are endowed with phosphorolytic ribonuclease activity residing in the RNase PH-like domains, the former is completely inactive. Instead, the exosome of Eukaryota has three hydrolytic ribonuclease activities, which are supplied by the associated subunits of the Dis3 and Rrp6 families. However, even though it has no

Part three: the exosome in vivo

Considering its complicated structure and array of catalytic activities, the exosome is far more than just another nuclease. It targets RNAs of virtually all classes at various stages of their lives, from maturation through constant quality control to final turnover. Its functions are, among others, maturation of 3′ ends of rRNA and snoRNAs, degradation of unstable RNAs generated by pervasive and read-through transcription, removal of excised introns and other RNA maturation by-products,

Conclusion

With its multi-subunit structure and three different ribonuclease activities, tightly regulated and applied to vastly different purposes (house-keeping and regulatory), the exosome is a truly amazing machine. While its importance was never questioned, it is only in recent years that its functional diversity has been fully appreciated, and still new surprising roles of the exosome are being uncovered [102], [103]. The various auxiliary systems that govern exosome substrate recruitment form an

Note added in proof

When this article was in press, a study by Makino et al. (http://dx.doi.org/10.1038/nature11870) revealed new information about the structure of the holoexosome of S. cerevisiae, specifically the binding site of Rrp6 and details of substrate threading through the core complex. We strongly suggest that the article be read along with this review.

Acknowledgements

ADZ's group is supported by National Science Center grants: 3339/B/P01/2010/39 and 2011/02/A/NZ1/00001. THJ's group is supported by the Danish National Research Foundation, the Novo Nordisk Foundation and the Danish Cancer Society. ML was supported by a PhD fellowship of the Boehringer Inhelgeim Fonds. The authors wish to thank Karolina Drążkowska for critical reading of the manuscript.

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