HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 41, 30431-30438, October 13, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/41/30431    most recent M605320200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Orsi, A. Articles by Sitia, R. Search for Related Content PubMed PubMed Citation Articles by Orsi, A. Articles by Sitia, R. Social Bookmarking                      What's this?

Conditions of Endoplasmic Reticulum Stress Favor the Accumulation of Cytosolic Prion Protein^*

Andrea Orsi, Luana Fioriti¹, Roberto Chiesa², and Roberto Sitia³

From the Università Vita-Salute San Raffaele, DiBiT Istituto Scientifico San Raffaele, Via Olgettina 58, 20132 Milano, Italy, and the Dulbecco Telethon Institute and Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy

After signal sequence-dependent targeting to the endoplasmic reticulum (ER), prion protein (PrP) undergoes several post-translational modifications, including glycosylation, disulfide bond formation, and the addition of a glycosylphosphatidylinositol anchor. As a result, multiple isoforms are generated. Because of the intrinsic weakness of the PrP signal sequence, a fraction of newly synthesized molecules fails to translocate and localizes to the cytosol. The physiopathologic role of this cytosolic isoform is still being debated. Here we have shown that, in both cultured cell lines and primary neurons, ER stress conditions weaken PrP co-translational translocation, favoring accumulation of aggregation-prone cytosolic species, which retain the signal sequence but lack N-glycans and disulfides. Inhibition of proteasomes further increases the levels of cytosolic PrP. Overexpression of spliced XBP1 facilitates ER translocation, suggesting that downstream elements of the Ire1-XBP1 pathway are involved in PrP targeting. These studies reveal a link between ER stress and the formation of cytosolic PrP isoforms potentially endowed with novel signaling or cytotoxic functions.

Received for publication, June 2, 2006 , and in revised form, August 14, 2006.

^* This work was supported in part through grants from the Associazione Italiana per la Ricerca sul Cancro, Fondazione Cariplo, Ministero della Sanità, Ministero dell'Istruzione Universitá e Ricerca and Telethon-Italy (S00083 to R. C.). 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 Supported by a fellowship from the Fondazione Monzino.

² An Assistant Telethon Scientist (Dulbecco Telethon Institute Foundation).

³ To whom correspondence should be addressed: Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy. Tel.: 39-02-26434763; Fax: 39-02-26434723; E-mail: r.sitia{at}hsr.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Linden, V. R. Martins, M. A. M. Prado, M. Cammarota, I. Izquierdo, and R. R. Brentani Physiology of the Prion Protein Physiol Rev, April 1, 2008; 88(2): 673 - 728. [Abstract] [Full Text] [PDF]

				C. Krammer, M. H. Suhre, E. Kremmer, C. Diemer, S. Hess, H. M. Schatzl, T. Scheibel, and I. Vorberg Prion protein/protein interactions: fusion with yeast Sup35p-NM modulates cytosolic PrP aggregation in mammalian cells FASEB J, March 1, 2008; 22(3): 762 - 773. [Abstract] [Full Text] [PDF]

				C. Hetz, A.-H. Lee, D. Gonzalez-Romero, P. Thielen, J. Castilla, C. Soto, and L. H. Glimcher Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis PNAS, January 15, 2008; 105(2): 757 - 762. [Abstract] [Full Text] [PDF]

				C. Hetz, J. Castilla, and C. Soto Perturbation of Endoplasmic Reticulum Homeostasis Facilitates Prion Replication J. Biol. Chem., April 27, 2007; 282(17): 12725 - 12733. [Abstract] [Full Text] [PDF]