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J. Biol. Chem., Vol. 279, Issue 19, 19441-19447, May 7, 2004

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Degradation of Wild-type Vasopressin Precursor and Pathogenic Mutants by the Proteasome^*

Michael A. Friberg, Martin Spiess, and Jonas Rutishauser

From the Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland, and the Department of Medicine, Medical Clinic A and Division of Endocrinology, Metabolism and Clinical Nutrition, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland

Mutations in the gene encoding the antidiuretic hormone arginine vasopressin cause autosomal dominant neurogenic diabetes insipidus. Autoptic data in affected individuals suggest that the neurons expressing mutant vasopressin undergo selective degeneration. Expression studies have shown that the mutants are retained in the endoplasmic reticulum, but how this trafficking defect is linked to neurotoxicity is unknown. One possibility is that unsecreted mutant precursors, or degradation products thereof, are cytotoxic. We therefore investigated the fate of endoplasmic reticulum-retained pathogenic mutants. Our data show that the mutants are retrotranslocated to the cytosol and degraded by the proteasome. In the presence of proteasomal inhibitors, three distinct un- or deglycosylated cytosolic species of vasopressin precursors were stabilized: pre-pro-vasopressin, pro-vasopressin, and an N-terminally truncated form. In addition to the retrotranslocated forms, a fraction of the newly synthesized precursor was not translocated, but was synthesized into the cytosol due to inefficient function of the vasopressin signal peptide. As a result, cytosolic pre-pro-vasopressin and its degradation product were also recovered when wild-type vasopressin was expressed. Cytosolic forms of vasopressin might trigger cytotoxicity in vivo, as has been proposed in the case of prion protein, which also contains an inefficient N-terminal signal peptide.

Received for publication, September 15, 2003 , and in revised form, February 5, 2004.

Note Added in Proof—A recent paper confirmed the neurodegeneration hypothesis in ADNDI using a murine knock-in model (Russel, T. A., Ito, M., Ito, M., Yu, R. N., Martinson, F. A., Weiss, J., and Jameson, J. L. (2003) J. Clin. Investig. 112, 1697–1706). Mice expressing the C67X neurophysin II mutation showed polyuria and polydipsia, which was paralleled by loss of neurons in the supraoptic and paraventricular nuclei. Neurodegeneration did not appear to be mediated by upregulation of CHOP protein levels.

^* This work was supported by Grants 32-061978.00 (to J. R.) and 31-061579.00 (to M. S.) from the Swiss National Science Foundation. 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.

To whom correspondence should be addressed: Medical Clinic B and Division of Endocrinology, Metabolism and Clinical Nutrition, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. Tel: 41-61-2654665; Fax: 41-61-2655100; E-mail: j.rutishauser{at}unibas.ch.

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