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J. Biol. Chem., Vol. 283, Issue 15, 9966-9976, April 11, 2008

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The Signal Peptide of the Mouse Mammary Tumor Virus Rem Protein Is Released from the Endoplasmic Reticulum Membrane and Accumulates in Nucleoli^*

Elisa Dultz¹², Markus Hildenbeutel¹³, Bruno Martoglio, Jacob Hochman^¶, Bernhard Dobberstein, and Katja Kapp⁴

From the Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), D-69120 Heidelberg, Germany, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland, and the ^¶Department of Cell and Animal Biology, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

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.

Received for publication, July 11, 2007 , and in revised form, February 5, 2008.

^* This work was supported by Grant SFB 638/A2 from the Deutsche Forschungsgemeinschaft (to B. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Present address: EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

³ Present address: AG Zellbiologie, TU Kaiserslautern, Erwin Schrödinger-Strasse 13, 67663 Kaiserslautern, Germany.

⁴ To whom correspondence should be addressed: ZMBH, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. Tel.: 49-6221-546823; Fax: 49-6221-545892; E-mail: k.kapp{at}zmbh.uni-heidelberg.de.

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