title: The signal peptide of the mouse mammary tumor virus Rem protein is released from the endoplasmic reticulum membrane and accumulates in nucleoli.
abstract: N-terminal signal sequences mediate endoplasmic reticulum (ER) targeting and insertion of nascent secretory and membrane proteins and are, in most cases, cleaved off by signal peptidase. The mouse mammary tumor virus envelope protein and its alternative splice variant Rem have an unusually long signal sequence, which contains a nuclear localization signal. Although the envelope protein is targeted to the ER, inserted, and glycosylated, Rem has been described as a nuclear protein. Rem as well as a truncated version identical to the cleaved signal sequence have been shown to function as nuclear export factors for intron-containing transcripts. Using transiently transfected cells, we found that Rem is targeted to the ER, where the C-terminal portion is translocated and glycosylated. The signal sequence is cleaved off and accumulates in nucleoli. In a cell-free in vitro system, the generation of the Rem signal peptide depends on the presence of microsomal membranes. In vitro and in cells, the signal peptide initially accumulates in the membrane and is subsequently released into the cytosol. This release does not depend on processing by signal peptide peptidase, an intramembrane cleaving protease that can mediate the liberation of signal peptide fragments from the ER membrane. Our study suggests a novel pathway by which a signal peptide can be released from the ER membrane to fulfill a post-targeting function in a different compartment.
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Mayerhofstrasse 1, Heidelberg, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Dultz
authors.forename: Markus
authors.initials: M
authors.lastname: Hildenbeutel
authors.forename: Bruno
authors.initials: B
authors.lastname: Martoglio
authors.forename: Jacob
authors.initials: J
authors.lastname: Hochman
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dobberstein
authors.forename: Katja
authors.initials: K
authors.lastname: Kapp
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism*; D046188:Protein Modification, Translational / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019913:Nuclear Localization Signals; D014759:Viral Envelope Proteins