Endocrinology, Diabetes and Hypertension

Ann Marie Zavacki, Ph.D.

In order for T3 to mediate its biological effects, the pro-hormone thyroxine (T4) must be activated by removal of one outer-ring iodine by the type 1 and 2 deiodinases (D1 and D2).  On the other hand, D1 and the type 3 deiodinase (D3) can inactivate T3 by removal of an inner-ring iodine to generate T2 or reverse T3 (rT3). Thus, the iodothyronine deiodinases play a very important role in controlling the amount of available T3 by regulating both its production and degradation. My research addresses how the deiodinases allow adaptability resulting in the maintenance of thyroid hormone homeostasis under a variety of physiological conditions.  Specifically, I am interested in compensatory mechanisms that allow the C3H-D2KO mouse that has no D2, and greatly reduced (1/10 normal) D1, to maintain normal serum T3 levels. Despite normal serum T3 levels, these mice have an increased T4 and TSH suggesting a central resistance to T4, and an increased body fat (30%), indicative of other tissue-specific defects that I am currently investigating.

The relatively modest phenotypical abnormalities found in the C3H-D2KO mouse suggest that the remaining deiodinase found in these animals, D3, must possess extraordinary adaptive capacity.  However, the importance of this T3-inactivating enzyme in regulating tissue-specific T3 levels has only recently been appreciated.  Little is known about the cell biology of this enzyme, and how this is linked to its physiological role.  Thus, I am also identifying D3 interacting proteins using two methods, 2 dimensional differential gel electrophoresis combined with mass spectrophotometry (2-D DIGE MS), and the yeast two-hybrid system, to provide a framework for investigating the mechanisms involved in the regulation of this enzyme.

1. Zavacki AM, Mansell JB, Chung M, Klimovitsky B, Harney JW, Berry MJ. Coupled tRNA^Sec dependent assembly of the selenocysteine decoding apparatus. 2003 Molecular Cell, 2003 Mar;11:773-781
2. Curcio-Morelli C, Zavacki AM, Christofollete M, Gereben B, de Freitas BCG, Harney JW, Li Z, Wu G, Bianco AC. Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation. 2003 J Clin Invest July;112(2):189-196
3. Kim BW, Zavacki AM, Curcio-Morelli C, Dentice M, Harney JW, Larsen PR, Bianco AC. ER-associated degredation of the human type 2 iodothyronine deiodinase (D2) is mediated via an association between mammalian UBC7 and the carboxyl region of D2. 2003 Mol Endocrinol Dec;17(12):2603-2612.
4. Zavacki AM, Ying H, Christoffolete MA, Aerts G, So E, Harney JW, Cheng SY, Larsen PR, Bianco AC.  Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse. 2005 Endocrinology; 146(3):1568-1575.