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Abstract
Hepatocyte odd protein shuttling (HOPS) moves between nucleus and cytoplasm. HOPS overexpression leads to cell cycle arrest in G0/G1, and HOPS knockdown causes centrosome alterations, with subsequent abnormal cell division. Recently, we demonstrated that HOPS acts as a functional bridge in NPM-p19Arf interactions. Here we show that HOPS is present in 3 different isoforms that play distinct intracellular functions. Although HOPS is a transmembrane ubiquitin, an isoform with intermediate molecular weight is cleaved from the membrane and released into the cytosol, to act as the shuttling protein. We identified a signal peptide peptidase structure in N-terminal membrane-bound HOPS that allows the regulated intramembrane proteolysis (RIP) system to control the relative amounts of the released, shuttling isoform capable of binding NPM. These results argue for distinct, isoform-specific functions of HOPS in the nucleolus, nucleus, and cytoplasm and provide insight into the dynamics of HOPS association with NPM, whose mutation and subsequent delocalization is found in 30% of acute myeloid leukemia patients.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgment
We thank Paolo Puccetti for critical reading of the manuscript, Silvano Pagnotta and Maria Luisa Alunni for technical assistance. The plasmid and mutant constructs of NPM were a generous gift of PG Pelicci (European Institute of Oncology). This study was supported by grants from PRIN Project n. 2010C2LKKJ_002 Associazione Umbra Contro il Cancro (AUCC) and Fondazione Cassa di Risparmio di Perugia. GS is recipient of a PRIN Project n. 2010C2LKKJ_002. DB, CB, and DP are recipient of AUCC fellowship program. MC and SP are recipient of fellowship POR OB 3 Misura D4.
