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Thyroid hormone receptor β sumoylation is required for thyrotropin regulation and thyroid hormone production.

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.

SUBMITTER: Ke S

PROVIDER: S-EPMC8410017 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Thyroid hormone receptor beta is required for thyrotrpin regulation and thyroid hormone production.

Project description:Thyroid hormone receptor beta (THRB) is post-translationally modified by small ubiquitin-like modifier (SUMO). To investigate the biological role of THRB sumoylation, we generated a mouse model with a mutation that disrupts sumoylation at lysine 146 (K146Q). The THRB K146Q mutant mice had normal serum thyroxine (T4), markedly elevated serum thyrotropin (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 concentration, indicated blunted feedback regulation of TSH. TH profuction was 10-fold lower (per mg of thyroid tissue) in mutant mice compared to Wt mice.

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