NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling

Abstract

At a first glance, ribosome biogenesis and chromatin remodeling are quite different processes, but they share a common problem involving interactions between charged nucleic acids and small basic proteins that may result in unwanted intracellular aggregations. The multifunctional nuclear acidic chaperone NPM1 (B23/nucleophosmin) is active in several stages of ribosome biogenesis, chromatin remodeling, and mitosis as well as in DNA repair, replication and transcription. In addition, NPM1 plays an important role in the Myc-ARF-p53 pathway as well as in SUMO regulation. However, the relative importance of NPM1 in these processes remains unclear. Provided herein is an update on the expanding list of the diverse activities and interacting partners of NPM1. Mechanisms of NPM1 nuclear export functions of NPM1 in the nucleolus and at the mitotic spindle are discussed in relation to tumor development. It is argued that the suggested function of NPM1 as a histone chaperone could explain several, but not all, of the effects observed in cells following changes in NPM1 expression. A future challenge is to understand how NPM1 is activated, recruited, and controlled to carry out its functions.

Figure 1

Structure of NPM1. (a) Domain representation of human NPM1, NPM2 and NPM3 proteins. Acidic patches (“A”) are indicated. (HD: heterodimerization domain, DBD: DNA binding domain, NoLS: nucleolar localization motif). (b) Pentamer structure of Xenopus laevis xNPM1/NO38 (PDB ID: 1XE0) as visualized in Jalview PDB viewer. (c) Two pentamers of human NPM1 (PDB ID: 2P1B) stacked in a decameric configuration. (d) Sequence alignment of the core region from different NPM1 proteins and NPM-like proteins. Clustal W was used for alignment and further editing was done with help of Chromas alignment software. The structurally important “AKDE” and “GSGP” loops are indicated in the figure as well as the location of conserved L42 and L102 residues (reference to human NPM1). Hs: Homo sapiens; Mm: Mus musculus; Rn: Rattus norvegicus; Dr: Danio rerio; Gg: Gallus gallus; Xl: Xenopus laevis; Dm: Drosophila melanogaster; Lp: Lytechinus pictus (sea urchin); Ap: Asterina pectinifera (star fish).

Figure 2

NPM1 domain organization. (a) Detailed domain representation of human NPM1 highlighting oligomerization, acidic, basic regions and where A1–A3 denotes the acidic patches (NLS: nuclear localization signal; HD: heterodimerization domain; DBD: DNA binding domain; NoLS: nucleolar localization motif). (b) Partial sequence alignment of NPM1.1 (wt) and the NPM1.2 and NPM1.3 isoforms illustrating loss of important parts of NPM1.

Figure 3

NPM1 is a multifunctional histone binding protein. NPM1 can affect DNA replication, repair and transcription by interacting with the components of chromatin such as histones and chromatin remodeling proteins. NPM1 is also required for a controlled progression through mitosis and NPM1 can promote ribosome biogenesis. These effects may arise through the ability of NPM1 to bind histones at the centromeres or in the nucleolus, respectively.