title: Thyroid hormone receptor isoform-specific modification by small ubiquitin-like modifier (SUMO) modulates thyroid hormone-dependent gene regulation.
abstract: 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 SUMO 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 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 TSHβ-negative TRE. SUMO3 was required for T3-stimulated TR binding to the TSHβ-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.
authors.affiliation: Molecular Endocrinology Laboratory, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA, Los Angeles, California 90073, USA. yyl@ucla.edu
authors.forename: Yan-Yun
authors.initials: YY
authors.lastname: Liu
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kogai
authors.forename: James J
authors.initials: JJ
authors.lastname: Schultz
authors.forename: Kaizeen
authors.initials: K
authors.lastname: Mody
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Brent
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020218:Response Elements / Q000502:physiology; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D037322:Thyrotropin, beta Subunit / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D020033:Protein Isoforms; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; C492189:SUMO3 protein, human; C529670:SUMO3 protein, rat; D025841:Small Ubiquitin-Related Modifier Proteins; C117908:Sumo3 protein, mouse; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D037322:Thyrotropin, beta Subunit; D014452:Ubiquitins; D014284:Triiodothyronine; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; C494365:Crebbp protein, rat