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.

Post-mitotic dynamics of pre-nucleolar bodies is driven by pre-ribosomal RNA processing

“…S2 for RPS29 knockdown). NPM/B23 was always observed in persistent PNBs, irrespective of the siRNA used, in agreement with the versatile function of this protein in the production of both ribosomal subunits (Lindström, 2011). The snoRNP protein fibrillarin and the U8 snoRNA, which participate in early maturation steps, were always absent from late PNBs (data not shown).…”

The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway

“…The Wnt target c-Myc drives RNA polymerases I-III transcription, which mediates ribosome biogenesis (16,17). Wnt signaling also directly regulates ribosome biogenesis by activating the expression of Peter Pan (PPAN), Pescadillo (PES), and nucleophosmin (NPM/B23), all of which are essential nucleolar components of the ribosome biogenesis machinery (3,18,19). All three factors are up-regulated in cancers with constitutively active Wnt signaling (20 -22).…”

“…It was demonstrated that PPAN, together with its interaction partner PES, regulates the maturation of the large ribosomal subunit in the nucleolus (18,25). NPM is a direct binding factor of PES and is required for ribosome formation (19,26). Besides, NPM is an anti-apoptotic factor regulating mitochondrial apoptosis (27).…”

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

“…10,15,16,23,24 Here, we focus on the C-terminal domain of the protein. We describe its structure, interactions, known physiological functions, and how they are modified in the NPM1 leukemic mutants.…”

“…14 The N-terminal domain has also been reported to mediate NPM1 interactions with a plethora of other proteins, including p53, p14arf, Fbw7c, APE-1, ribosomal proteins RPL5, RPS9, RPL23, HIV proteins REV and TAT, and many others. 10,15,16 Through these interactions, none of which has been structurally characterized, NPM1 functions extend considerably beyond its role as a histone chaperone. 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.…”