Nucleolar targeting: the hub of the matter

Abstract

The nucleolus is a dynamic structure that has roles in various processes, from ribosome biogenesis to regulation of the cell cycle and the cellular stress response. Such functions are frequently mediated by the sequestration or release of nucleolar proteins. Our understanding of protein targeting to the nucleolus is much less complete than our knowledge of membrane-spanning translocation systems-such as those involved in nuclear targetingand the experimental evidence reveals that few parallels exist with these better-characterized systems. Here, we discuss the current understanding of nucleolar targeting, explore the types of sequence that control the localization of a protein to the nucleolus, and speculate that certain subsets of nucleolar proteins might act as hub proteins that are able to bind to multiple protein targets. In parallel to other subnuclear structures, such as PML bodies, the proteins that are involved in the formation and maintenance of the nucleolus are inexorably linked to nucleolar trafficking. Keywords: hub protein; nucleolar localization; nucleolin; nucleolus; nucleophosmin EMBO reports (2009) 10, 231-238. doi:10.1038/embor.2009.14 See Glossary for abbreviations used in this article. IntroductionThe nucleus is a highly ordered structure that contains non-membranebound subcompartments-including PML bodies, splicing speckles, Cajal bodies and the nucleolus-that have specific functions. The nucleolus is the largest subnuclear structure (Fig 1) and is easily visible under the light microscope owing to its high refractive index. It is centred on rDNA repeats within the chromosomes and is traditionally assoc iated with ribosome biogenesis. In mammalian cells, the number and activity of nucleoli vary during the cell cycle according to differing metabolic conditions and cell types.The mammalian nucleolus can be morphologically divided into several discrete regions-the fibrillar centre (FC), the dense fibrillar centre (DFC) and the granular component (GC)-that have roles in the various steps of rRNA synthesis. The FC contains the trans cription factor UBF and is rich in RNA polymerase I. The DFCs are associated with, and surround, the FCs and contain fibrillarin, an RNA methyltransferase and nucleolin-a protein that has multiple roles in nucleolar and cellular biology . Surrounding both the FC and the DFC is the GC, which is the site of the partial maturation and assembly of pre-ribosomes, accumulates NPM, and is enriched with ribosomal proteins and assembly factors. The GC might also contain regions that comprise protein complexes that are devoid of RNA (Politz et al, 2005).Our understanding of nucleolar function changed markedly with the formulation of the plurifunctional nucleolus hypothesis (Pederson, 1998), which has now been underpinned by proteomic analysis (Boisvert et al, 2007), and proposes that the nucleolus has multiple functions in health and disease (Matthews & Olson, 2006;Stark & Taliansky, 2009). For example, there is extensive evidence that the nucleolus is involved in the respo...

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

“…The expression levels of these proteins correlate with the tumorigenicity of MCF-7 cells that express mutant p14. In recent years, it has been established that in addition to its role in rRNA synthesis and ribosome biogenesis, the nucleolus is involved in a variety of cellular functions, including regulation of the cell cycle, senescence, gene silencing, and sensing of cellular stress (26)(27)(28)(29)(30)(31), as well as in viral replication (32,33). The relationship between the nucleolus, ribosome biogenesis, and cancer has been the topic of a recent review (34), in which some evidence to that effect has been documented.…”

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

“…As a histone chaperone, NPM1 binds most efficiently to acetylated H3/H4 heterodimers and, as mentioned above, is able to promote the activities of nucleosome remodeling complexes and to support transcription and chromatin packaging activities (Okuwaki et al 2001;Swaminathan et al 2005). The ability of NPM1 to interact with highly positive sequences, along with its oligomerization activity have D r a f t 9 led several groups to propose that NPM1 may be the scaffolding protein responsible for retention of proteins containing arginine/lysine-rich nucleolar localization signals (NoLSs) within the nucleolus (Emmott and Hiscox 2009;Li et al 1996;Mitrea et al 2016). Through its C-terminal regions, NPM1 is able to bind short ssDNA sequences and promote dsDNA strand annealing (Borggrefe et al 1998) and, independently of those functions, to also interact with structured RNAs in response to genotoxic stress (Yang et al 2002).…”

Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

“…Importantly, although most of the identified NoLS are formed by sequence motives enriched in consecutive basic residues, 17 which are thought to be recognized by specific nucleolar hub proteins (including NPM1), the NoLS of NPM1 is unique and constituted by the two tryptophan residues in helix H3. This was initially shown by observing that deletion of the terminal 288-294 segment in NPM1, which includes the two tryptophans [ Fig.…”

“…Many of these proteins show nucleolar localization and it has been proposed that NPM1 favors their correct cellular localization, trafficking, stability, and activity, thus behaving as a nucleolar hub protein. 17 The N-terminal domain is followed in NPM1 by a 120-residue long central domain, which is predicted to be natively unstructured throughout its length (Fig. 1).…”