Liu YY, Kogai T, Schultz JJ, Mody K, Brent GA

Thyroid hormone receptor (TR) α and β mediate thyroid hormone action at target tissues. TR isoforms have specific roles in development and in adult tissues. The mechanisms underlying TR isoform-specific action, however, are not well understood. We demonstrate that posttranslational modification of TR by conjugation of small ubiquitin-like modifier (SUMO) ...

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to TRα and TRβ plays an important role in triiodothyronine (T3) action and TR isoform-specificity. TRα was sumoylated at lysines 283 and 389, and TRβ at lysines 50, 146 and 443. Sumoylation of TRβ was ligand-dependent and sumoylation of TRα was ligand-independent. TRα-SUMO conjugation utilized the E3 ligase PIASxβ and TRβ-SUMO conjugation utilized predominantly PIAS1. SUMO1 and SUMO3 conjugation to TR was important for T3-dependent gene regulation, as demonstrated in transient transfection assay and studies of endogenous gene regulation. The functional role of SUMO1 and SUMO3 in T3-induction in transient expression assays was closely matched to the pattern of TR and co-factor recruitment to thyroid hormone response elements (TREs) as determined by Chromatin Immunoprecipitation (ChIP) assays. SUMO1 was required for the T3-induced recruitment of the co-activator CREB-binding protein (CBP) and release of co-repressor (NCoR) on a TRE, but had no significant effect on TR DNA binding. SUMO1 was required for T3-mediated recruitment of NCoR and release of CBP from the TSHβ negative TRE (nTRE). SUMO3 was required for T3-stimulated TR binding to the nTRE and recruitment of NCoR. These findings demonstrate that conjugation of SUMO to TR has a TR-isoform preference and is important for T3-dependent gene induction and repression.

Date: Aug. 28, 2012

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