Antonio C. Bianco, MD, PhD
Photo: Antonio C. Bianco



Elected 2005
In all vertebrates, thyroid hormone can be activated or inactivated in a stage- and tissue-specific manner by iodothyronine deiodinases. The type 2 deiodinase, D2, generates T3 from the prohormone T4 in the perinuclear space, increasing the supply of T3 to the cell nucleus. Targeted disruption of the Dio2 gene in mice impairs cochlear development, pituitary thyroid-stimulating hormone (TSH) feedback, and adaptive thermogenesis, while myocardial overexpression of D2 causes chronic cardiac-specific thyrotoxicosis. As is typical for selenocysteine-containing proteins, the biosynthesis of D2 is inefficient, such that regulation of D2 activity is achieved primarily by ubiquitination. In eukaryotic cells, covalent attachment of mono- or polyubiquitin chains is a critical method by which the function and fate of proteins may be altered. For endoplasmic reticulum (ER)-resident proteins such as D2, this regulatory mechanism is referred to as ER-associated degradation (ERAD). Ubiquitination inactivates D2 and targets the protein for degradation in the proteasomes. A unique enzyme that acts as a D2-specific E3 ubiquitin ligase mediates this. Structural and mutational analyses indicate that this protein recognizes a novel destruction sequence in D2 that confers metabolic instability. This process is accelerated during deiodination of T4, presumably as a result of conformational changes during catalysis. As a consequence, the half-life of D2 can vary from 10 to 300 minutes depending on the rate of T4 deiodination. Remarkably, inactive ubiquitinated D2 can be reactivated by the pVHL-interacting deubiquitinating enzymes (VDU). This highly dynamic, reversible mechanism integrates developmental, environmental, and homeostatic signals to control thyroid hormone action.