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J. Biol. Chem., Vol. 282, Issue 9, 6183-6191, March 2, 2007

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Oxidoreductase Interactions Include a Role for ERp72 Engagement with Mutant Thyroglobulin from the rdw/rdw Rat Dwarf^*

Shekar Menon, Jaemin Lee, William A. Abplanalp, Sung-Eun Yoo, Takashi Agui^¶, Sen-ichi Furudate^||, Paul S. Kim, and Peter Arvan¹

From the Program in Cell and Molecular Biology and Division of Endocrinology, University of Cincinnati, Ohio 45267, the ^¶Laboratory of Experimental Animal Science, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan, the ^||Department of Laboratory Animal Science, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan, and the Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Newly synthesized thyroglobulin (Tg), the secretory glycoprotein that serves as precursor in thyroid hormone synthesis, normally forms transient covalent protein complexes with oxidoreductases of the endoplasmic reticulum (ER). The Tg-G2320R mutation is responsible for congenital hypothyroidism in rdw/rdw rats, in which a lack of secondary thyroid enlargement (goiter) implicates death of thyrocytes as part of disease pathogenesis. We found that mutant Tg-G2320R was retained within the ER with no detectable synthesis of thyroxine, had persistent exposure of free cysteine thiols, and was associated with activated ER stress response but incomplete ER-associated degradation (ERAD). Tg-G2320R associated with multiple ER resident proteins, most notably ERp72, including covalent Tg-ERp72 interactions. In PC Cl3 thyrocytes, inducible overexpression of ERp72 increased the ability of cells to maintain Tg cysteines in a reduced state. Noncovalent interactions of several ER chaperones with newly synthesized Tg-G2320R diminished over time in parallel with ERAD of the mutant protein, yet a small ERAD-resistant Tg fraction remained engaged in covalent association with ERp72 even 2 days post-synthesis. Such covalent protein aggregates may set the stage for apoptotic thyrocyte cell death, preventing thyroid goiter formation in rdw/rdw rats.

Received for publication, September 14, 2006 , and in revised form, December 4, 2006.

^* This work was supported by National Institutes of Health Grants DK40344 (to P. A.) and DK52076 (to P. S. K.) and a Veterans Affairs Merit Award (to P. S. K.). 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: Div. of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, 5560 MSRB2, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0678. Tel.: 734-936-5505; Fax: 718-936-6684; E-mail: parvan{at}umich.edu.

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