Different functions of HOPS isoforms in the cell: HOPS shuttling isoform is determined by RIP cleavage system.
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.
Department of Clinical and Experimental Medicine; University of Perugia; Perugia, Italy.
Marilena
M
Castelli
Department of Clinical and Experimental Medicine; University of Perugia; Perugia, Italy.
Danilo
D
Piobbico
Department of Clinical and Experimental Medicine; University of Perugia; Perugia, Italy.
Daniela
D
Bartoli
Department of Clinical and Experimental Medicine; University of Perugia; Perugia, Italy.
Stefania
S
Pieroni
Department of Clinical and Experimental Medicine; University of Perugia; Perugia, Italy.
Cinzia
C
Brunacci
Department of Clinical and Experimental Medicine; University of Perugia; Perugia, Italy.
Marina Maria
MM
Bellet
Department of Clinical and Experimental Medicine; University of Perugia; Perugia, Italy.
Martina
M
Chiacchiaretta
Department of Clinical and Experimental Medicine; University of Perugia; Perugia, Italy.
Maria Agnese
MA
Della Fazia
Department of Clinical and Experimental Medicine; University of Perugia; Perugia, Italy.
Giuseppe
G
Servillo
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D009928:Organ Specificity; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism
D002352:Carrier Proteins; C531356:HOPS protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000597888:Tmub1 protein, rat; D025801:Ubiquitin; D000090243:Nucleophosmin
hepatocyte odd protein shuttling; intramembrane-cleaving proteases (iCliPs)/shuttling protein; nucleophosmin; transmembrane and ubiquitin-like domain containing 1; tumor suppressor gene/regulated intramembrane proteolysis (RIP) system