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J. Biol. Chem., Vol. 283, Issue 24, 16446-16454, June 13, 2008

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A Dual Task for the Xbp1-responsive OS-9 Variants in the Mammalian Endoplasmic Reticulum

INHIBITING SECRETION OF MISFOLDED PROTEIN CONFORMERS AND ENHANCING THEIR DISPOSAL^*

From the Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland

Normally, non-native polypeptides are not transported through the secretory pathway. Rather, they are translocated from the endoplasmic reticulum (ER) lumen into the cytosol where they are degraded by proteasomes. Here we characterize the function in ER quality control of two proteins derived from alternative splicing of the OS-9 gene. OS-9.1 and OS-9.2 are ubiquitously expressed in human tissues and are amplified in tumors. They are transcriptionally induced upon activation of the Ire1/Xbp1 ER-stress pathway. OS-9 variants do not associate with folding-competent proteins. Rather, they selectively bind folding-defective ones thereby inhibiting transport of non-native conformers through the secretory pathway. The intralumenal level of OS-9.1 and OS-9.2 inversely correlates with the fraction of a folding-defective glycoprotein, the Null_{hong kong} (NHK) variant of 1-antitrypsin that escapes retention-based ER quality control. OS-9 up-regulation does not affect NHK disposal, but reduction of the intralumenal level of OS-9.1 and OS-9.2 substantially delays disposal of this model substrate. OS-9.1 and OS-9.2 also associate transiently with non-glycosylated folding-defective proteins, but association is unproductive. Finally, OS-9 activity does not require an intact mannose 6-P homology domain. Thus, OS-9.1 and OS-9.2 play a dual role in mammalian ER quality control: first as crucial retention factors for misfolded conformers, and second as promoters of protein disposal from the ER lumen.

Received for publication, March 21, 2008 , and in revised form, April 9, 2008.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by grants from Foundation for Research on Neurodegenerative Diseases, Fondazione San Salvatore, Swiss National Center of Competence in Research on Neural Plasticity and Repair, Swiss National Science Foundation, Synapsis Foundation, Bangerter-Rhyner Foundation and Aetas. To whom correspondence should be addressed. Tel.: 04191-8200319; Fax: 04191-8200305; E-mail: maurizio.molinari{at}irb.unisi.ch.

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