Abstract
Thyroid hormone receptor β (THRB) is posttranslationally modified by small ubiquitin-like modifier (SUMO). We generated a mouse model with a mutation that disrupted sumoylation at lysine 146 (K146Q) and resulted in desumoylated THRB as the predominant form in tissues. The THRB K146Q mutant mice had normal serum thyroxine (T4), markedly elevated serum thyrotropin-stimulating hormone (TSH; 81-fold above control), and enlargement of both the pituitary and the thyroid gland. The marked elevation in TSH, despite a normal serum T4, indicated blunted feedback regulation of TSH. The THRB K146Q mutation altered the recruitment of transcription factors to the TSHβ gene promoter, compared with WT, in hyperthyroidism and hypothyroidism. Thyroid hormone content (T4, T3, and rT3) in the thyroid gland of the THRB K146Q mice was 10-fold lower (per gram tissue) than control, despite normal TSH bioactivity. The expression of thyroglobulin and dual oxidase 2 genes in the thyroid was reduced and associated with modifications of cAMP response element–binding protein DNA binding and cofactor interactions in the presence of the desumoylated THRB. Therefore, thyroid hormone production had both TSH-dependent and TSH-independent components. We conclude that THRB sumoylation at K146 was required for normal TSH feedback regulation and TH synthesis in the thyroid gland, by a TSH-independent pathway.
Highlights
Thyroid hormone (TH) exerts its biological and physiological actions primarily through interaction with the nuclear TH receptor (THR; refs. 1, 2)
K50 residue is located in the amino terminus (A/B domain); K438 residue is located in the ligand-binding domain; and K146 residue is located in the second zinc finger of the DNA-binding domain (DBD; Figure 1B)
We evaluated the influence of the K146Q mutation on the ability of THRB1 to mediate triiodothyronine-induced (T3-induced) transcription, utilizing a luciferase reporter with a consensus direct repeat with 4 base pair gap TH response element (DR4-TRE)
Summary
Thyroid hormone (TH) exerts its biological and physiological actions primarily through interaction with the nuclear TH receptor (THR; refs. 1, 2). THR β (THRB) is expressed in liver, heart, and pituitary and mediates the regulation of cholesterol metabolism, as well as the feedback regulation of thyrotropin-stimulating hormone (TSH) in the pituitary. The regulation of TSHβ gene expression involves multiple transcription factors (TFs) in addition to THRB, including GATA-binding protein 2 (GATA2) and Pit 1/POU1F1 [6,7,8,9,10,11,12]. The role of these TFs, has largely been based on transient reporter expression assays rather than direct determination of in vivo binding to the TSHβ gene regulatory regions [11]. GATA2 is important for both stimulation and repression of TSHβ gene expression [9, 14]
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