Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 43, Pages 36499-36508Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.344317
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- Veterans Affairs Merit Review Funds
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Thyroid hormone receptor (TR) alpha and beta 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 smallSUMOtoTR alpha and TR beta plays an important role in triiodothyronine (T3) action and TR isoform specificity. TR alpha was sumoylated at lysines 283 and 389, and TR beta at lysines 50, 146, and 443. Sumoylation of TR beta was ligand-dependent, and sumoylation of TR alpha was ligand-independent. TR alpha-SUMO conjugation utilized the E3 ligase PIASx beta and TR beta-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 cofactor recruitment to thyroid hormone response elements (TREs) as determined by ChIP assays. SUMO1 was required for the T3-induced recruitment of the co-activator CREB-binding protein (CBP) and release of nuclear receptor 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 TSH beta-negative TRE. SUMO3 was required for T3-stimulated TR binding to the TSH beta-negative TRE 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.
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