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Ubiquitinated deiodinase: not dead yet
Ronald J. Koenig
Endocrinology Division, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA
Address correspondence to: Ronald J. Koenig, University of Michigan Medical Center, 5560 Medical Science Research Building II, 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109-0678, USA. Phone: (734) 763-3056; Fax: (734) 936-6684; E-mail: rkoenig@umich.edu.
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Published July 15, 2003 - More info
J Clin Invest. 2003;112(2):145–147. https://doi.org/10.1172/JCI19157.
© 2003 The American Society for Clinical Investigation
Thyroxine (T4), the major secretory product of the thyroid gland, is a prohormone. Removal of an outer-ring iodine by either type 1 or type 2 iodothyronine deiodinase (D1, D2) yields the biologically active hormone 3,5,3′-triiodothyronine (T3). The deiodinases are interesting enzymes. For example, their catalytic sites contain the rare amino acid selenocysteine, encoded by UGA, which under ordinary circumstances functions as a stop codon (1, 2).
D2 is particularly fascinating (see ref. 3 for an outstanding review). In rodents, it is expressed primarily in brown adipose tissue (BAT), brain, and pituitary, and also in the developing cochlea. In humans, D2 is expressed somewhat more broadly, including in skeletal muscle, heart, and thyroid. Approximately 50% of nuclear T3 receptors (TRs) are ligand-occupied in most tissues of euthyroid rats. However, a substantially higher fraction of the TRs of tissues that express D2 are ligand-occupied — from 75% in BAT to 97% in cerebral cortex. This extra T3 is generated locally by D2 from plasma-derived T4. In contrast, T3 generated by D1 does not have direct access to nuclei but instead must first be exported into the plasma. The difference appears to relate to the subcellular localization of these enzymes; D2 is an ER enzyme localized to the perinuclear space, whereas D1 lies in the plasma membrane (4). Thus, although both D1 and D2 contribute to the plasma T3, D2 provides an additional local source of nuclear T3. The consequence is that D2-containing organs can regulate their nuclear TR occupancy independent of the plasma T3 level. It follows, then, that local regulation of D2 activity is critically important in determining the thyroid status of D2-containing organs, and that plasma T4 is an important source of nuclear T3 in these organs.
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Reactivation of Ub-D2 by deubiquitinases
Although Ub-D2 is catalytically inactive, it exists in a netherworld, poised to be degraded in the black hole of the proteasome, or, potentially, to be reactivated by deubiquitination. In this issue of the JCI, Curcio-Morelli et al. (8) demonstrate that D2 interacts with von Hippel–Lindau protein–interacting deubiquitinating enzymes-1 and -2 (VDU1 and VDU2), and that these interactions prolong the D2 half-life and rejuvenate enzyme activity by deubiquitinating Ub-D2. Remarkably, VDU1 is induced rapidly in BAT by cold exposure or norepinephrine, providing a new mechanism to achieve local saturation of TRs and hence an adequate thermogenic response to cold (Figure 1). Reactivation of Ub-D2 may be a particularly valuable mechanism for this selenoprotein, as it avoids the need to resynthesize D2. Incorporation of selenocysteine at UGA codons is inefficient and decreases translation efficiency about 100-fold (9).
Figure 1Thyroid hormone metabolism and action in different cell types. (a) Hepatocytes (which express D1), as a model for cells that do not express D2. D1 converts plasma T4 to T3, but this T3 does not have direct access to the cell nucleus. Plasma T3 enters the nucleus. In the euthyroid state, TRs are about 50% T3-occupied and target genes are induced proportionately. (b) BAT, as a model for tissues that express D2. Plasma T3 enters the nucleus. In addition, the ER enzyme D2 converts T4 to T3, which has direct access to the nucleus, resulting in a high level of TR occupancy by T3. Target genes are induced proportionately. D2 is regulated by metabolic perturbations, e.g., cold exposure (via norepinephrine) in BAT. The catalytic activity of D2 stimulates its ubiquitination and potential degradation in proteasomes. However, the VDUs can prevent degradation and recover enzyme activity by deubiquitinating Ub-D2. In BAT, VDU1 itself is induced by cold exposure, via norepinephrine. In some tissues, VDUs are ubiquitinated by pVHL and degraded, but this has not been studied in BAT. The retinoid X receptor (RXR) is the dimerization partner for TR.
D2 is the first specific substrate identified for the VDUs, and this is the first example of enzyme reactivation by deubiquitination. The VDUs are the first ubiquitin-specific processing enzymes shown to specifically deubiquitinate an ERAD substrate. What, actually, are the VDUs? The von Hippel–Lindau protein (pVHL) is a component of an E3 ubiquitin ligase that plays a role in determining substrate specificity for ubiquitination (10, 11). Mutations in the VHL gene are associated with the autosomal dominant tumor syndrome von Hippel–Lindau disease (characterized by CNS and retinal hemangioblastomas, renal clear cell carcinomas, pheochromocytomas, and others) as well as sporadic renal carcinomas. VDU1 was identified by yeast two-hybrid screen as a pVHL-interacting protein (12), and VDU2 was identified by homology to VDU1 (13). Both VDUs are ubiquitinated by the pVHL E3 ligase and are themselves deubiquitinases, suggesting that pVHL-mediated degradation of VDUs regulates the ubiquitin-proteasome pathway. Since pVHL stimulates degradation of VDUs, there is a potential link between pVHL (which is widely expressed) and decreased local T3 generation by D2.
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