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J. Biol. Chem., Vol. 281, Issue 42, 31538-31543, October 20, 2006

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Metabolic Instability of Type 2 Deiodinase Is Transferable To Stable Proteins Independently of Subcellular Localization^*

Anikó Zeöld, Lívia Pormüller, Monica Dentice, John W. Harney, Cyntia Curcio-Morelli, Susana M. Tente, Antonio C. Bianco, and Balázs Gereben¹

From the Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony Street 43, Budapest H-1083, Hungary and Thyroid Section, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard University Medical School, Boston, Massachusetts 02115

Thyroid hormone activation is catalyzed by two deiodinases, D1 and D2. Whereas D1 is a stable plasma membrane protein, D2 is resident in the endoplasmic reticulum (ER) and has a 20-min half-life due to selective ubiquitination and proteasomal degradation. Here we have shown that stable retention explains D2 residency in the ER, a mechanism that is nevertheless over-ridden by fusion to the long-lived plasma membrane protein, sodium-iodine symporter. Fusion to D2, but not D1, dramatically shortened sodium-iodine symporter half-life through a mechanism dependent on an 18-amino acid D2-specific instability loop. Similarly, the D2-specific loop-mediated protein destabilization was also observed after D2, but not D1, was fused to the stable ER resident protein SEC62. This indicates that the instability loop in D2, but not its subcellular localization, is the key determinant of D2 susceptibility to ubiquitination and rapid turnover rate. Our data also show that the 6 N-terminal amino acids, but not the 12 C-terminal ones, are the ones required for D2 recognition by WSB-1.

Received for publication, May 17, 2006 , and in revised form, August 21, 2006.

^* This work was supported by National Institutes of Health Grants TW006467, DK58538, and DK36246 and by Hungarian Scientific Research Fund Grant OTKA T49081. [GenBank] 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 To whom correspondence should be addressed. Tel.: 36-1-210-9946; Fax: 36-1-210-9961; E-mail: gereben{at}koki.hu.

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