Biosynthesis of prion protein nucleocytoplasmic isoforms by alternative initiation of translation.
The cellular prion protein PrP(C) is synthesized as a family of four distinct forms. Of these, (Cyt)PrP is a minor member that segregates outside of the secretory route and can generate cytotoxic forms. Using signal sequence mutants, we found that (Cyt)PrP is translated from a downstream AUG (coding for Met-8 in human PrP or Met-15 in Syrian hamster PrP). Shortening of the signal sequence dictated the spillage of this isoform into the cytosol, from where it accessed the nucleus or formed insoluble cytosolic aggregates if the proteasome is inhibited. The PrP isoform isolated from the nuclear fractions of cell and brain homogenates was partially SUMO-1-conjugated. Expression of HaPrP(M15) in cells caused an antiproliferative phenotype due to a cell cycle arrest at the G(0)/G(1) phase. The identification of this PrP isoform and its properties provides novel insight into PrP(C) physiological and pathological functions.
Juanes
María E
ME
Instituto de Química-Física "Rocasolano, Consejo Superior de Investigaciones Científicas (CSIC)," Serrano 119, 28006 Madrid.
Elvira
Gema
G
Instituto de Química-Física "Rocasolano, Consejo Superior de Investigaciones Científicas (CSIC)," Serrano 119, 28006 Madrid.
García-Grande
Aranzazu
A
Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029 Madrid.
Calero
Miguel
M
Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Pozuelo Km 2, 28220 Majadahonda, Madrid, Spain.
Gasset
María
M
Instituto de Química-Física "Rocasolano, Consejo Superior de Investigaciones Científicas (CSIC)," Serrano 119, 28006 Madrid. Electronic address: mgasset@iqfr.csic.es.
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D047468:Immunoprecipitation; D008647:Mesocricetus; D008715:Methionine / Q000737:chemistry; D011328:Prions / Q000096:biosynthesis* / Q000737:chemistry; D020033:Protein Isoforms / Q000096:biosynthesis* / Q000737:chemistry
D017931:DNA Primers; D011328:Prions; D020033:Protein Isoforms; D008715:Methionine