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Eur Thyroid J. 2016 Sep;5(3):152-163. Epub 2016 Aug 4.

Impaired Repressor Function in SUMOylation-Defective Thyroid Hormone Receptor Isoforms.

Author information

1
Institute of Reproductive Biology, Leibniz Institute for Farm Animal Biology (FBN), FBN Dummerstorf, Dummerstorf, Germany.

Abstract

BACKGROUND:

Many nuclear receptors are modified by posttranslational modifications.

OBJECTIVES:

The transcriptional activity of thyroid hormone receptors (TRs) is modified by the influence of its ligand (thyroid hormones T3 and T4), but is also affected by posttranslational modifications. This study focuses on the SUMOylation of TR isoforms and the consequences on transcriptional activity and promoter occupancy.

METHODS:

SUMOylation of TR wild-type as well as isoform-specific point mutations have been studied in vitro. The promoter occupancy of TR (wild-type and double- or triple-mutated versions) and transcriptional cofactors have been investigated in chromatin immunoprecipitation (ChIP) and Re-ChIP analysis.

RESULTS:

TR is modified by SUMO proteins at defined residues: the isoform TRα is mainly modified at lysines 281 and 387, whereas lysines 50 and 443 are major SUMOylation sites of isoform TRβ. Lysine residues K281 (TRα) and K50 (TRβ) are isoform-specific SUMOylation sites influencing differing TR domains, whereas K387 (TRα) and K443 (TRβ) are orthologous residues. TRs are targets of all three SUMO variants (SUMO-1, -2, and -3). The transcriptional activity of SUMOylation-defective mutants of TR alters gene transcription from positively and negatively regulated T3 target genes.

CONCLUSIONS:

The most pronounced effect is an impaired repressor function of SUMOylation-deficient TR in the absence of T3. The transcriptional properties of SUMOylation-defective TRs can be at least in part ascribed to altered interaction with transcriptional cofactors such as SRC-1 and NCoR. Thus, these data indicate that posttranslational modification of TR by SUMOylation contribute to the fine tuning of its transcriptional response maintaining effects on cellular and physiological homeostasis.

KEYWORDS:

Gene expression; Ligand-dependent transcription factor; Posttranslational modification; SUMO; Transrepression

PMID:
27843805
PMCID:
PMC5091228
[Available on 2017-03-01]
DOI:
10.1159/000447232

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