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The Deiodinase Trio and Thyroid Hormone Signaling

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Thyroid Hormone Nuclear Receptor

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1801))

Abstract

Thyroid hormone signaling is customized in a time and cell-specific manner by the deiodinases, homodimeric thioredoxin fold containing selenoproteins. This ensures adequate T3 action in developing tissues, healthy adults and many disease states. D2 activates thyroid hormone by converting the pro-hormone T4 to T3, the biologically active thyroid hormone. D2 expression is tightly regulated by transcriptional mechanisms triggered by endogenous as well as environmental cues. There is also an on/off switch mechanism that controls D2 activity that is triggered by catalysis and functions via D2 ubiquitination/deubiquitination. D3 terminates thyroid hormone action by inactivation of both T4 and T3 molecules. Deiodinases play a role in thyroid hormone homeostasis, development, growth and metabolic control by affecting the intracellular levels of T3 and thus gene expression on a cell-specific basis. In many cases, tight control of these pathways by T3 is achieved with coordinated reciprocal changes in D2-mediated thyroid hormone activation D3-mediated thyroid hormone inactivation.

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References

  1. Galton VA (2005) The roles of the iodothyronine deiodinases in mammalian development. Thyroid 15(8):823–834

    Article  PubMed  CAS  Google Scholar 

  2. Larsen PR (1982) Thyroid-pituitary interaction: feedback regulation of thyrotropin secretion by thyroid hormones. N Engl J Med 306(1):23–32

    Article  PubMed  CAS  Google Scholar 

  3. Christoffolete MA, Ribeiro R, Singru P, Fekete C, da Silva WS, Gordon DF et al (2006) Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism. Endocrinology 147(4):1735–1743

    Article  PubMed  CAS  Google Scholar 

  4. Fekete C, Gereben B, Doleschall M, Harney JW, Dora JM, Bianco AC et al (2004) Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: implications for the nonthyroidal illness syndrome. Endocrinology 145(4):1649–1655

    Article  PubMed  CAS  Google Scholar 

  5. Huang SA, Bianco AC (2008) Reawakened interest in type III iodothyronine deiodinase in critical illness and injury. Nat Clin Pract Endocrinol Metab 4(3):148–155

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Peeters RP, Visser TJ (2000) In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM et al (eds) Endotext. South Dartmouth, MA

    Google Scholar 

  7. Galton VA (2017) The ups and downs of the thyroxine pro-hormone hypothesis. Mol Cell Endocrinol 458:105–111

    Article  PubMed  CAS  Google Scholar 

  8. Arrojo EDR, Fonseca TL, Werneck-de-Castro JP, Bianco AC (2013) Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochim Biophys Acta 1830(7):3956–3964

    Article  CAS  Google Scholar 

  9. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23(1):38–89

    Article  PubMed  CAS  Google Scholar 

  10. Callebaut I, Curcio-Morelli C, Mornon JP, Gereben B, Buettner C, Huang S et al (2003) The iodothyronine selenodeiodinases are thioredoxin-fold family proteins containing a glycoside hydrolase clan GH-A-like structure. J Biol Chem 278(38):36887–36896

    Article  PubMed  CAS  Google Scholar 

  11. Sagar GD, Gereben B, Callebaut I, Mornon JP, Zeöld A, Curcio-Morelli C et al (2008) The thyroid hormone-inactivating deiodinase functions as a homodimer. Mol Endocrinol 22(6):1382–1393

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Baqui M, Botero D, Gereben B, Curcio C, Harney JW, Salvatore D et al (2003) Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and undergoes rapid internalization to endosomes. J Biol Chem 278(2):1206–1211

    Article  PubMed  CAS  Google Scholar 

  13. Schweizer U, Schlicker C, Braun D, Kohrle J, Steegborn C (2014) Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism. Proc Natl Acad Sci U S A 111(29):10526–10531

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Darras VM, Van Herck SL (2012) Iodothyronine deiodinase structure and function: from ascidians to humans. J Endocrinol 215(2):189–206

    Article  PubMed  CAS  Google Scholar 

  15. Safran M, Leonard JL (1991) Comparison of the physicochemical properties of type I and type II iodothyronine 5′-deiodinase. J Biol Chem 266(5):3233–3238

    PubMed  CAS  Google Scholar 

  16. Leonard JL, Visser TJ, Leonard DM (2001) Characterization of the subunit structure of the catalytically active type I iodothyronine deiodinase. J Biol Chem 276(4):2600–2607

    Article  PubMed  CAS  Google Scholar 

  17. Curcio-Morelli C, Gereben B, Zavacki AM, Kim BW, Huang S, Harney JW et al (2003) In vivo dimerization of types 1, 2, and 3 iodothyronine selenodeiodinases. Endocrinology 144(3):937–946

    Article  PubMed  CAS  Google Scholar 

  18. Sagar GD, Gereben B, Callebaut I, Mornon JP, Zeold A, da Silva WS et al (2007) Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity. Mol Cell Biol 27(13):4774–4783

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Visser WE, Friesema EC, Visser TJ (2011) Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol 25(1):1–14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S (2004) A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 74(1):168–175

    Article  PubMed  CAS  Google Scholar 

  21. Friesema EC, Kuiper GG, Jansen J, Visser TJ, Kester MH (2006) Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Mol Endocrinol 20(11):2761–2772

    Article  PubMed  CAS  Google Scholar 

  22. Cheng SY, Leonard JL, Davis PJ (2010) Molecular aspects of thyroid hormone actions. Endocr Rev 31(2):139–170

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS et al (2008) Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 29(7):898–938

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Galton VA (1992) The role of thyroid hormone in amphibian metamorphosis. Trends Endocrinol Metab 3(3):96–100

    Article  PubMed  CAS  Google Scholar 

  25. Nguyen TT, Chapa F, JJ DS 3rd (1998) Direct measurement of the contributions of type I and type II 5′-deiodinases to whole body steady state 3,5,3′-triiodothyronine production from thyroxine in the rat. Endocrinology 139(11):4626–4633

    Article  PubMed  CAS  Google Scholar 

  26. Abdalla SM, Bianco AC (2014) Defending plasma T3 is a biological priority. Clin Endocrinol 81(5):633–641

    Article  CAS  Google Scholar 

  27. Schneider MJ, Fiering SN, Thai B, Wu SY, St Germain E, Parlow AF et al (2006) Targeted disruption of the type 1 selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone economy in mice. Endocrinology 147(1):580–589

    Article  PubMed  CAS  Google Scholar 

  28. Gereben B, Goncalves C, Harney JW, Larsen PR, Bianco AC (2000) Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation. Mol Endocrinol 14(11):1697–1708

    Article  PubMed  CAS  Google Scholar 

  29. Baqui MM, Gereben B, Harney JW, Larsen PR, Bianco AC (2000) Distinct subcellular localization of transiently expressed types 1 and 2 iodothyronine deiodinases as determined by immunofluorescence confocal microscopy. Endocrinology 141(11):4309–4312

    Article  PubMed  CAS  Google Scholar 

  30. Steinsapir J, Bianco AC, Buettner C, Harney J, Larsen PR (2000) Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme’s active center. Endocrinology 141(3):1127–1135

    Article  PubMed  CAS  Google Scholar 

  31. Kim BW, Zavacki AM, Curcio-Morelli C, Dentice M, Harney JW, Larsen PR et al (2003) Endoplasmic reticulum-associated degradation of the human type 2 iodothyronine deiodinase (D2) is mediated via an association between mammalian UBC7 and the carboxyl region of D2. Mol Endocrinol 17(12):2603–2612

    Article  PubMed  CAS  Google Scholar 

  32. Botero D, Gereben B, Goncalves C, De Jesus LA, Harney JW, Bianco AC (2002) Ubc6p and ubc7p are required for normal and substrate-induced endoplasmic reticulum-associated degradation of the human selenoprotein type 2 iodothyronine monodeiodinase. Mol Endocrinol 16(9):1999–2007

    Article  PubMed  CAS  Google Scholar 

  33. Dentice M, Bandyopadhyay A, Gereben B, Callebaut I, Christoffolete MA, Kim BW et al (2005) The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Nat Cell Biol 7(7):698–705

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Zavacki AM, Arrojo E, Drigo R, Freitas BC, Chung M, Harney JW, Egri P et al (2009) The E3 ubiquitin ligase TEB4 mediates degradation of type 2 iodothyronine deiodinase. Mol Cell Biol 29(19):5339–5347

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Curcio-Morelli C, Zavacki AM, Christofollete M, Gereben B, de Freitas BC, Harney JW et al (2003) Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation. J Clin Invest 112(2):189–196

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Li Z, Na X, Wang D, Schoen SR, Messing EM, Wu G (2002) Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein. J Biol Chem 277(7):4656–4662

    Article  PubMed  CAS  Google Scholar 

  37. Komander D, Clague MJ, Urbé S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10(8):550–563

    Article  PubMed  CAS  Google Scholar 

  38. Fekete C, Freitas BC, Zeöld A, Wittmann G, Kádár A, Liposits Z et al (2007) Expression patterns of WSB-1 and USP-33 underlie cell-specific posttranslational control of type 2 deiodinase in the rat brain. Endocrinology 148(10):4865–4874

    Article  PubMed  CAS  Google Scholar 

  39. Werneck de Castro JP, Fonseca TL, Ueta CB, McAninch EA, Abdalla S, Wittmann G et al (2015) Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest 125(2):769–781

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hetz C, Saxena S (2017) ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol 13(8):477–491

    Article  PubMed  CAS  Google Scholar 

  41. Schröder M (2008) Endoplasmic reticulum stress responses. Cell Mol Life Sci 65(6):862–894

    Article  PubMed  CAS  Google Scholar 

  42. Meusser B, Hirsch C, Jarosch E, Sommer T (2005) ERAD: the long road to destruction. Nat Cell Biol 7(8):766–772

    Article  PubMed  CAS  Google Scholar 

  43. Vembar SS, Brodsky JL (2008) One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9(12):944–957

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Arrojo e Drigo R, Fonseca TL, Castillo M, Salathe M, Simovic G, Mohacsik P et al (2011) Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eIF2a-mediated decrease in type 2 deiodinase synthesis. Mol Endocrinol 25(12):2065–2075

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Bartha T, Kim SW, Salvatore D, Gereben B, Tu HM, Harney JW et al (2000) Characterization of the 5′-flanking and 5′-untranslated regions of the cyclic adenosine 3′,5′-monophosphate-responsive human type 2 iodothyronine deiodinase gene. Endocrinology 141(1):229–237

    Article  PubMed  CAS  Google Scholar 

  46. Canettieri G, Celi FS, Baccheschi G, Salvatori L, Andreoli M, Centanni M (2000) Isolation of human type 2 deiodinase gene promoter and characterization of a functional cyclic adenosine monophosphate response element. Endocrinology 141(5):1804–1813

    Article  PubMed  CAS  Google Scholar 

  47. Bianco AC, Kieffer JD, Silva JE (1992) Adenosine 3′,5′-monophosphate and thyroid hormone control of uncoupling protein messenger ribonucleic acid in freshly dispersed brown adipocytes. Endocrinology 130(5):2625–2633

    Article  PubMed  CAS  Google Scholar 

  48. da-Silva WS, Harney JW, Kim BW, Li J, Bianco SD, Crescenzi A et al (2007) The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. Diabetes 56(3):767–776

    Article  PubMed  CAS  Google Scholar 

  49. Houten SM, Watanabe M, Auwerx J (2006) Endocrine functions of bile acids. EMBO J 25(7):1419–1425

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H et al (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439(7075):484–489

    Article  PubMed  CAS  Google Scholar 

  51. da-Silva WS, Ribich S, Arrojo e Drigo R, Castillo M, Patti ME, Bianco AC (2011) The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure. FEBS Lett 585(3):539–544

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Bates JM, St Germain DL, Galton VA (1999) Expression profiles of the three iodothyronine deiodinases, D1, D2, and D3, in the developing rat. Endocrinology 140(2):844–851

    Article  PubMed  CAS  Google Scholar 

  53. Galton VA, Schneider M, Clark AS, Germain DL (2009) Life without T4 to T3 conversion: studies in mice devoid of the 5′-deiodinases. Endocrinology 150(6):2957–2963

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. St Germain DL, Hernandez A, Schneider MJ, Galton VA (2005) Insights into the role of deiodinases from studies of genetically modified animals. Thyroid 15(8):905–916

    Article  PubMed  CAS  Google Scholar 

  55. Ng L, Goodyear RJ, Woods CA, Schneider MJ, Diamond E, Richardson GP et al (2004) Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase. Proc Natl Acad Sci U S A 101(10):3474–3479

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Gouveia CH, Christoffolete MA, Zaitune CR, Dora JM, Harney JW, Maia AL et al (2005) Type 2 iodothyronine selenodeiodinase is expressed throughout the mouse skeleton and in the MC3T3-E1 mouse osteoblastic cell line during differentiation. Endocrinology 146(1):195–200

    Article  PubMed  CAS  Google Scholar 

  57. Miura M, Tanaka K, Komatsu Y, Suda M, Yasoda A, Sakuma Y et al (2002) Thyroid hormones promote chondrocyte differentiation in mouse ATDC5 cells and stimulate endochondral ossification in fetal mouse tibias through iodothyronine deiodinases in the growth plate. J Bone Miner Res 17(3):443–454

    Article  PubMed  CAS  Google Scholar 

  58. Bassett JH, Boyde A, Howell PG, Bassett RH, Galliford TM, Archanco M et al (2010) Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts. Proc Natl Acad Sci U S A 107(16):7604–7609

    Article  PubMed  PubMed Central  Google Scholar 

  59. Capelo LP, Beber EH, Huang SA, Zorn TM, Bianco AC, Gouveia CH (2008) Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton. Bone 43(5):921–930

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Hall JA, Ribich S, Christoffolete MA, Simovic G, Correa-Medina M, Patti ME et al (2010) Absence of thyroid hormone activation during development underlies a permanent defect in adaptive thermogenesis. Endocrinology 151(9):4573–4582

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Dentice M, Marsili A, Ambrosio R, Guardiola O, Sibilio A, Paik JH et al (2011) The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration. J Clin Invest 120(11):4021–4030

    Article  CAS  Google Scholar 

  62. Ignacio DL, Silvestre DH, Anne-Palmer E, Bocco BM, Fonseca TL, Ribeiro MO et al (2017) Early developmental disruption of type 2 deiodinase pathway in mouse skeletal muscle does not impair muscle function. Thyroid 27(4):577–586

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Fonseca TL, Fernandes GW, McAninch EA, Bocco BM, Abdalla SM, Ribeiro MO et al (2015) Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity. Proc Natl Acad Sci U S A 112(45):14018–14023

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Chiamolera MI, Wondisford FE (2009) Minireview: thyrotropin-releasing hormone and the thyroid hormone feedback mechanism. Endocrinology 150(3):1091–1096

    Article  PubMed  CAS  Google Scholar 

  65. Schneider MJ, Fiering SN, Pallud SE, Parlow AF, St Germain DL, Galton VA (2001) Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol 15(12):2137–2148

    Article  PubMed  CAS  Google Scholar 

  66. Rosene ML, Wittmann G, Arrojo e Drigo R, Singru PS, Lechan RM, Bianco AC (2010) Inhibition of the type 2 iodothyronine deiodinase underlies the elevated plasma TSH associated with amiodarone treatment. Endocrinology 151(12):5961–5970

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Freitas BC, Gereben B, Castillo M, Kalló I, Zeöld A, Egri P et al (2010) Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells. J Clin Invest 120(6):2206–2217

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Fonseca TL, Correa-Medina M, Campos MP, Wittmann G, Werneck-de-Castro JP, Arrojo-e-Drigo R et al (2013) Coordination of hypothalamic and pituitary T3 production regulates TSH expression. J Clin Invest 123(4):1492–1500

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. McAninch EA, Bianco AC (2014) Thyroid hormone signaling in energy homeostasis and energy metabolism. Ann N Y Acad Sci 1311:77–87

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Preite NZ, Nascimento BP, Muller CR, Americo AL, Higa TS, Evangelista FS et al (2016) Disruption of beta3 adrenergic receptor increases susceptibility to DIO in mouse. J Endocrinol 231(3):259–269

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Fernandes GW, Ueta CB, Fonseca TL, Gouveia CH, Lancellotti CL, Brum PC et al (2014) Inactivation of the adrenergic receptor beta2 disrupts glucose homeostasis in mice. J Endocrinol 221(3):381–390

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Ueta CB, Fernandes GW, Capelo L, Fonseca TL, Maculan FD, Gouveia C et al (2012) beta1 adrenergic receptor is key to cold- and diet-induced thermogenesis in mice. J Endocrinol 214(3):359–365

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Carvalho SD, Kimura ET, Bianco AC, Silva JE (1991) Central role of brown adipose tissue thyroxine 5′-deiodinase on thyroid hormone-dependent thermogenic response to cold. Endocrinology 128(4):2149–2159

    Article  PubMed  CAS  Google Scholar 

  74. Branco M, Ribeiro M, Negrao N, Bianco AC (1999) 3,5,3′-Triiodothyronine actively stimulates UCP in brown fat under minimal sympathetic activity. Am J Phys 276(1 Pt 1):E179–E187

    CAS  Google Scholar 

  75. de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW et al (2001) The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest 108(9):1379–1385

    Article  PubMed  PubMed Central  Google Scholar 

  76. Castillo M, Hall JA, Correa-Medina M, Ueta C, Won Kang H, Cohen DE et al (2011) Disruption of thyroid hormone activation in type 2 deiodinase knockout mice causes obesity with glucose intolerance and liver steatosis only at thermoneutrality. Diabetes 60(4):1082–1089

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Fonseca TL, Werneck-De-Castro JP, Castillo M, Bocco BM, Fernandes GW, McAninch EA et al (2014) Tissue-specific inactivation of type 2 deiodinase reveals multilevel control of fatty acid oxidation by thyroid hormone in the mouse. Diabetes 63(5):1594–1604

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Lartey LJ, Werneck-de-Castro JP, O-Sullivan I, Unterman TG, Bianco AC (2015) Coupling between nutrient availability and thyroid hormone activation. J Biol Chem 290(51):30551–30561

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Galton VA, Wood ET, St Germain EA, Withrow CA, Aldrich G, St Germain GM et al (2007) Thyroid hormone homeostasis and action in the type 2 deiodinase-deficient rodent brain during development. Endocrinology 148(7):3080–3088

    Article  PubMed  CAS  Google Scholar 

  80. Barez-Lopez S, Bosch-Garcia D, Gomez-Andres D, Pulido-Valdeolivas I, Montero-Pedrazuela A, Obregon MJ et al (2014) Abnormal motor phenotype at adult stages in mice lacking type 2 deiodinase. PLoS One 9(8):e103857

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Bocco BM, Werneck-de-Castro JP, Oliveira KC, Fernandes GW, Fonseca TL, Nascimento BP et al (2016) Type 2 deiodinase disruption in astrocytes results in anxiety-depressive-like behavior in male mice. Endocrinology 157(9):3682–3695

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Barez-Lopez S, Montero-Pedrazuela A, Bosch-Garcia D, Venero C, Guadano-Ferraz A (2017) Increased anxiety and fear memory in adult mice lacking type 2 deiodinase. Psychoneuroendocrinology 84:51–60

    Article  PubMed  Google Scholar 

  83. Vassallo P, Trohman RG (2007) Prescribing amiodarone: an evidence-based review of clinical indications. JAMA 298(11):1312–1322

    Article  PubMed  CAS  Google Scholar 

  84. Pachucki J, Hopkins J, Peeters R, Tu H, Carvalho SD, Kaulbach H et al (2001) Type 2 iodothyronine deiodinase transgene expression in the mouse heart causes cardiac-specific thyrotoxicosis. Endocrinology 142(1):13–20

    Article  PubMed  CAS  Google Scholar 

  85. Carvalho-Bianco SD, Kim BW, Zhang JX, Harney JW, Ribeiro RS, Gereben B et al (2004) Chronic cardiac-specific thyrotoxicosis increases myocardial beta-adrenergic responsiveness. Mol Endocrinol 18(7):1840–1849

    Article  PubMed  CAS  Google Scholar 

  86. Trivieri MG, Oudit GY, Sah R, Kerfant BG, Sun H, Gramolini AO et al (2006) Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction. Proc Natl Acad Sci U S A 103(15):6043–6048

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME et al (2009) Type 2 deiodinase expression is induced by peroxisomal proliferator-activated receptor-gamma agonists in skeletal myocytes. Endocrinology 150(4):1976–1983

    Article  PubMed  CAS  Google Scholar 

  88. Dentice M, Marsili A, Ambrosio R, Guardiola O, Sibilio A, Paik JH et al (2010) The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration. J Clin Invest 120(11):4021–4030

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Bocco BM, Louzada RA, Silvestre DH, Santos MC, Anne-Palmer E, Rangel IF et al (2016) Thyroid hormone activation by type 2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression in skeletal muscle. J Physiol 594(18):5255–5269

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Baqui M, Botero D, Gereben B, Curcio C, Harney JW, Salvatore D et al (2003) Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and undergoes rapid internalization to endosomes. J Biol Chem 278(2):1206–1211

    Article  PubMed  CAS  Google Scholar 

  91. Salvatore D, Low SC, Berry M, Maia AL, Harney JW, Croteau W et al (1995) Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme. J Clin Invest 96(5):2421–2430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Hernandez A, Fiering S, Martinez E, Galton VA, St Germain D (2002) The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts. Endocrinology 143(11):4483–4486

    Article  PubMed  CAS  Google Scholar 

  93. Structure HA (2005) function of the type 3 deiodinase gene. Thyroid 15(8):865–874

    Article  Google Scholar 

  94. Dentice M, Salvatore D (2011) Local impact of thyroid hormone inactivation. J Endocrinol 209(3):273–282

    Article  PubMed  CAS  Google Scholar 

  95. Huang SA, Bianco AC (2008) Reawakened interest in type III iodothyronine deiodinase in critical illness and injury. Nat Clin Pract Endocrinol Metab 4(3):148–155

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Huang SA (2005) Physiology and pathophysiology of type 3 deiodinase in humans. Thyroid 15(8):875–881

    Article  PubMed  CAS  Google Scholar 

  97. Fliers E, Bianco AC, Langouche L, Boelen A (2015) Thyroid function in critically ill patients. Lancet Diabetes Endocrinol 3(10):816–825

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Jo S, Kallo I, Bardoczi Z, Arrojo EDR, Zeold A, Liposits Z et al (2012) Neuronal hypoxia induces hsp40-mediated nuclear import of type 3 deiodinase as an adaptive mechanism to reduce cellular metabolism. J Neurosci 32(25):8491–8500

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Huang SA, Mulcahey MA, Crescenzi A, Chung M, Kim B, Barnes CA et al (2005) TGF-B promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase. Mol Endocrinol 19:3126–3136

    Article  PubMed  CAS  Google Scholar 

  100. Dentice M, Luongo C, Huang S, Ambrosio R, Elefante A, Mirebeau-Prunier D et al (2007) Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes. Proc Natl Acad Sci U S A 104(36):14466–14471

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Medina MC, Fonesca TL, Molina J, Fachado A, Castillo M, Dong L et al (2014) Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic beta-cells and disrupts glucose homeostasis. Endocrinology 155(8):3160–3171

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Medina MC, Molina J, Gadea Y, Fachado A, Murillo M, Simovic G et al (2011) The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion. Endocrinology 152(10):3717–3727

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G (2003) Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 88(7):3202–3211

    Article  PubMed  CAS  Google Scholar 

  104. Ueta CB, Oskouei BN, Olivares EL, Pinto JR, Correa MM, Simovic G et al (2012) Absence of myocardial thyroid hormone inactivating deiodinase results in restrictive cardiomyopathy in mice. Mol Endocrinol 26(5):809–818

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Olivares EL, Marassi MP, Fortunato RS, da Silva AC, Costa-e-Sousa RH, Araujo IG et al (2007) Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study. Endocrinology 148(10):4786–4792

    Article  PubMed  CAS  Google Scholar 

  106. Wassen FW, Schiel AE, Kuiper GG, Kaptein E, Bakker O, Visser TJ et al (2002) Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure. Endocrinology 143(7):2812–2815

    Article  PubMed  CAS  Google Scholar 

  107. Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ et al (2008) Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats. J Clin Invest 118(3):975–983

    PubMed  PubMed Central  CAS  Google Scholar 

  108. Paolino BS, Pomerantzeff PM, Dallan LAO, Gaiotto FA, Preite NZ, Latronico AC et al (2017) Myocardial inactivation of thyroid hormones in patients with aortic stenosis. Thyroid 27(5):738–745

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, Kozakewich HP et al (2000) Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 343(3):185–189

    Article  PubMed  CAS  Google Scholar 

  110. Kappers MH, van Esch JH, Smedts FM, de Krijger RR, Eechoute K, Mathijssen RH et al (2011) Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression. J Clin Endocrinol Metab 96(10):3087–3094

    Article  PubMed  CAS  Google Scholar 

  111. Maynard MA, Marino-Enriquez A, Fletcher JA, Dorfman DM, Raut CP, Yassa L et al (2014) Thyroid hormone inactivation in gastrointestinal stromal tumors. N Engl J Med 370(14):1327–1334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Bianco AC, Anderson G, Forrest D, Galton VA, Gereben B, Kim BW et al (2014) American thyroid association guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 24(1):88–168

    Article  PubMed  PubMed Central  Google Scholar 

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The authors thank NIDDK for support.

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Correspondence to Antonio C. Bianco .

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Bianco, A.C., da Conceição, R.R. (2018). The Deiodinase Trio and Thyroid Hormone Signaling. In: Plateroti, M., Samarut, J. (eds) Thyroid Hormone Nuclear Receptor. Methods in Molecular Biology, vol 1801. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7902-8_8

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  • DOI: https://doi.org/10.1007/978-1-4939-7902-8_8

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