Different functions of HOPS isoforms in the cell HOPS shuttling isoform is determined by RIP cleavage system

作者：Castelli Marilena; Piobbico Danilo; Bartoli Daniela; Pieroni Stefania; Brunacci Cinzia; Bellet Marina Maria; Chiacchiaretta Martina; Della Fazia Maria Agnese^*; Servillo Giuseppe

来源：Cell Cycle, 2014, 13(2): 293-302.

DOI：10.4161/cc.27054

• hepatocyte odd protein shuttling
• nucleophosmin
• transmembrane and ubiquitin-like domain containing 1
• tumor suppressor gene/regulated intramembrane proteolysis (RIP) system
• intramembrane-cleaving proteases (iCliPs)/shuttling protein

Hepatocyte odd protein shuttling (HOPS) moves between nucleus and cytoplasm. HOPS overexpression leads to cell cycle arrest in G(0)/G(1), and HOPS knockdown causes centrosome alterations, with subsequent abnormal cell division. Recently, we demonstrated that HOPS acts as a functional bridge in NPM-p19(Arf) 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.

• 出版日期2014-1-15