Thyroid Hormone Receptor Isoform-Specific Actions

甲状腺激素受体亚型特异性作用

• 批准号: 9222005
• 负责人: GREGORY A BRENT
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222005
• 关键词: Adipocytes; Adult; Amino Acids; Amphibia; Binding; Binding Sites; Biological Assay; Biological Metamorphosis; Body Composition; Body Weight; Body Weight decreased; Catecholamines; Cell physiology; Cholesterol; Cholesterol Homeostasis; Consensus; Development; Dominant-Negative Mutation; Dyslipidemias; Energy Metabolism; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Growth; Hydrophobicity; Infusion procedures; Lead; Ligands; Liver X Receptor; Lysine; Mammals; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Mus; Mutant Strains Mice; Mutation; Nuclear; Nuclear Hormone Receptors; Nuclear Receptors; Obesity; PPAR alpha; Pathway interactions; Pattern; Peroxisome Proliferator-Activated Receptors; Pharmacology; Phenotype; Play; Post-Translational Protein Processing; Protein Isoforms; Proteins; Recruitment Activity; Regulation; Reporting; Repression; Respiration; Rest; Role; Signal Pathway; Signal Transduction; Site; Specificity; Thermogenesis; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormone Receptor Gene; Thyroid Hormones; Thyroid hormone receptor alpha; Tissues; Transfection; Triiodothyronine; Ubiquitin; adipocyte differentiation; chromatin immunoprecipitation; cofactor; gene induction; gene repression; genome-wide; hormone regulation; in vitro Model; knock-down; lipid biosynthesis; metabolic rate; mouse model; mutant; novel; perilipin; public health relevance; relating to nervous system; response; therapeutic target; transcription factor; ubiquitin-protein ligase; uncoupling protein 1

DESCRIPTION (provided by applicant): Thyroid hormone is essential for normal development, growth, neural differentiation, and metabolic regulation in mammals, and is required for amphibian metamorphosis. There are two thyroid hormone receptor (TR) genes, TRα and TRβ, with different patterns of expression in development and in adult tissues. The relevance of TR isoform specificity is strongly supported by the distinct phenotypes reported in families heterozygous for dominant negative mutations of the TRβ gene and TRα gene. The mechanism of TR isoform-specific action, however, is not well understood. Posttranslational modification of nuclear receptors is being increasingly recognized as an important mechanism of gene regulation. Most proteins modified by small ubiquitin-like modifier (SUMO) are transcription factors and nuclear hormone receptors. Sumoylation requires conjugation of SUMO to a lysine within the consensus recognition motif ψ-Lys-X-Glu (ψ is a large hydrophobic amino acid) of a protein, which rapidly and dynamically modifies proteins involved in cellular processes. We determined that posttranslational modification of TR by conjugation of SUMO to TRα at lysines 283 and 389, and TRβ at lysines 50, 146 and 443, plays an essential role in triiodothyronine (T3)-induced gene induction and repression as well as TR isoform-specificity. TRα-SUMO conjugation is ligand-independent and utilizes the E3 ligase PIASxb. TRβ-SUMO is ligand-dependent and utilizes predominantly the E3 ligase PIAS1. SUMO1 and SUMO3 conjugation to TR are required for T3-dependent gene regulation, as demonstrated in transient transfection assay and studies of endogenous gene regulation. The role of SUMO1 and SUMO3 in T3-induction in transient functional assays is closely matched to the pattern of TR and co-factor binding in regulation of endogenous genes, as determined by Chromatin Immunoprecipitation (ChIP) assays. Co-repressors play an essential role in thyroid hormone action, and TR sumoylation is important for co-repressor recruitment. We have demonstrated that TR sumoylation is important for thyroid hormone-regulated metabolic actions including adipocyte differentiation and cross-talk with important metabolic regulators including LXR and PPARα. Specific aims that will be pursued include; 1. Utilize in vitro models to determine the role of TR sumoylation and TRα/TRβ isoform-specific actions in metabolic regulation. 2. Determine how sumoylation modulates TR-mediated gene regulation including TR interaction with transcription co-factors, metabolic signaling pathways, and recognition and binding to T3-regulated genes. 3. Evaluate the influence of TRα and TRβ sumoylation site mutations on thyroid hormone regulation of metabolism in a mouse model. We will assess the impact of introducing TRα (K389Q) and TRβ (K443Q) gene sumoylation mutations on the thyroid hormone axis, tissue level thyroid status, and metabolic regulation. Understanding the role of TR sumoylation in metabolic regulation and TR-isoform specific action may lead to the identification of novel thyroid hormone signaling targets relevant to therapies for metabolic diseases, including dyslipidemia and obesity.

描述（由适用提供）：甲状腺马酮对于哺乳动物中的正常发育，生长，中性分化和代谢调节至关重要，并且是两栖动物变形所必需的。有两个甲状腺马酮受体（TR）基因TRα和TRβ，在发育和成人组织中具有不同的表达方式。 TR同工型特异性的相关性得到了在杂合家族中报道的对于TRβ基因和TRα基因的显性阴性突变的不同表型的强烈支持。但是，尚不清楚TR同工型特异性作用的机制。核受体的翻译后修饰越来越被认为是基因调节的重要机制。大多数由小型泛素样修饰剂（SUMO）修饰的蛋白质是转录因子和核骑手受体。 Sumoylation需要在共识识别基序中的赖氨酸偶联链酯基序中的赖氨酸，该蛋白质是一种大的蛋白质疏水性氨基酸），该蛋白质迅速且动态地改变了参与细胞过程的蛋白质。我们确定通过在283和389的SUMO与TRα的结合以及50、146和443的TRβ对TR的翻译后修饰，在三碘甲醇（T3）诱导的基因诱导和表达以及TR同工型特异性中起着至关重要的作用。 TRα-SUMO结合是不依赖配体的，并利用E3连接酶PIASXB。 TRβ-SUMO是配体依赖性的，主要利用E3连接酶PIAS1。 SUMO1和SUMO3与TR的共轭是T3依赖性基因调节所必需的，如瞬态转染测定和内源基因调节的研究所示。 SUMO1和SUMO3在T3诱导中在瞬态功能测定中的作用与TR和Co-Factor结合的模式与内源基因调节中的模式紧密匹配，如染色质免疫沉淀（CHIP）测定所确定。共抑制剂在甲状腺同性恋动作中起着至关重要的作用，而TR sumoylation对共抑制招募至关重要。我们已经证明，Tr sumoylation对于甲状腺同源调节的代谢作用至关重要，包括脂肪细胞分化和与重要的代谢调节剂在内，包括LXR和PPARα。将要追求的具体目标包括； 1。利用体外模型来确定TR sumoylation和TRα/TRβ同工型特异性作用在代谢调节中的作用。 2。确定Sumoylation如何调节TR介导的基因调节，包括与转录co因子，代谢信号通路以及识别和与T3调节基因的结合的相互作用。 3。评估TRα和TRβSumoylation位点突变对小鼠模型中代谢的甲状腺赛酮调节的影响。我们将评估引入TRα（K389Q）和TRβ（K443Q）基因Sumoylation突变对甲状腺骑马轴，组织水平甲状腺状态和代谢调节的影响。了解TR Sumoylation在代谢调节和特异性作用中的作用可能会导致鉴定与代谢性疾病疗法有关的新型甲状腺骑马信号传导靶标，包括血脂异常和肥胖症。

项目成果

Persistent COUP-TFII expression underlies the myopathy and impaired muscle regeneration observed in resistance to thyroid hormone-alpha.

• DOI: 10.1038/s41598-021-84080-5
• 发表时间: 2021-02-25
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Aguiari P;Liu YY;Petrosyan A;Cheng SY;Brent GA;Perin L;Milanesi A
• 通讯作者: Milanesi A

Beam Me In: Thyroid Hormone Analog Targets Alternative Transporter in Mouse Model of X-Linked Adrenoleukodystrophy.

向我发送信息：甲状腺激素类似物靶向 X 连锁肾上腺脑白质营养不良小鼠模型中的替代转运蛋白。

• DOI: 10.1210/en.2017-00206
• 发表时间: 2017
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Milanesi,Anna;Brent,GregoryA
• 通讯作者: Brent,GregoryA

Thyroid hormone receptor sumoylation is required for preadipocyte differentiation and proliferation.

甲状腺激素受体苏酰化是前脂肪细胞分化和增殖所必需的。

• DOI: 10.1074/jbc.m114.600312
• 发表时间: 2015
• 期刊: The Journal of biological chemistry
• 作者: Liu,Yan-Yun;Ayers,Stephen;Milanesi,Anna;Teng,Xiaochun;Rabi,Sina;Akiba,Ysutada;Brent,GregoryA
• 通讯作者: Brent,GregoryA