Hepatocyte odd protein shuttling (HOPS) is a bridging protein in the nucleophosmin-p19Arf network

Abstract

Nucleophosmin (NPM), a ubiquitously and abundantly expressed protein, occurs in the nucleolus, shuttling between the nucleoplasm and cytoplasm. The NPM gene is mutated in almost 30% of human acute myeloid leukemia cells. NPM interacts with p53 and p19(Arf), directs localization of p19(Arf) in the nucleolus and protects the latter from degradation. Hepatocyte odd protein shuttling (HOPS) is also a ubiquitously expressed protein that moves between the nucleus and cytoplasm. Within the nucleus of resting cells, HOPS overexpression causes cell cycle arrest in G0/G1. HOPS knockdown causes centrosome hyperamplification leading to multinucleated cells and the formation of micronuclei. We demonstrate a direct interaction of HOPS with NPM and p19(Arf), resulting in a functionally active trimeric complex. NPM appeared to regulate HOPS half-life, which, in turn, stabilized p19(Arf) and controlled its localization in the nucleolus. These findings suggest that HOPS acts as a functional bridge in the interaction between NPM and p19(Arf), providing new mechanistic insight into how NPM and p19(Arf) will oppose tumor cell proliferation.

Different functions of HOPS isoforms in the cell

“…10 HOPS, indeed, shares a number of functions with NPM, 15,23-25 a biologically relevant protein, which, if mutated, has a prominent role in the pathogenesis of AML. 16,17,26 Furthermore, HOPS is actively translocated in the cytoplasm by a mutated form of NPM once transfected in double-KO MEFs p53/NPM cells.…”

“…16,17,26 Furthermore, HOPS is actively translocated in the cytoplasm by a mutated form of NPM once transfected in double-KO MEFs p53/NPM cells. 10,27 We co-immunoprecipitated HOPS and different mutant forms of HOPS with NPM. While lHOPS would bind NPM as previously described, sHOPS failed to do so, demonstrating that the interaction between the 2 proteins involves the first 54 amino acids.…”

“…10 For IP, COS-1 cells, transfected with HOPS and HOPS mutants cDNAs, were lysed in RIPA buffer with Protease Inhibitor Cocktail (Sigma-Aldrich). Extracted proteins were quantified by Bio-Rad assay protein (Bio-Rad Laboratories), and immunoprecipitated with PG124 antibody overnight.…”

“…A role for HOPS was established in the control of p19 stability mediated by NPM. 10 At present, however, little is known of overall HOPS structure and functions.…”

Impaired cell proliferation in regenerating liver of 3 β-hydroxysterol Δ14-reductase (TM7SF2) knock-out mice

“…1 Furthermore, many other genes, some of which have been uncharacterized thus far, increase their expression or are modulated during liver regeneration. Among those are genes identified and/or studied by our group, such as Hops, [8][9][10][11] Lal-1, 12 Gucd-1, 13 Crem/Creb, 5-7 CD44, 14 and Tat. 15 An active metabolism of lipids occurs in the liver, whose correct functioning ensures normal liver regeneration.…”