The Deiodinase Trio and Thyroid Hormone Signaling
Open accessAbstract
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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L-T4 is solely produced by the thyroid gland and serves as a prohormone, while T3 is in part secreted by the thyroid gland and mainly generated in extra-thyroidal tissues by either type 1 or type 2 deiodinase (DIO1, DIO2).
“A century of thyroxine research has led to the commonly held opinion in the thyroid hormone community that 3,3′,5,5′-tetraiodo-L-thyronine (L-Thyroxine, L-T4), which is solely produced by the thyroid gland, serves as a prohormone while T3 (3,3′5-triiodo-L-thyronine), in part secreted by the thyroid gland, is mainly generated in various extra-thyroidal tissues by either type 1 or type 2 deiodinase”
From 3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action (2020) · cites this paper as [1]
The Introduction says T4 is the main hormone produced by the thyroid gland, is minimally active, and is converted to T3 mostly outside the gland. The Fundamental Aspects section identifies D1 as a contributor to extrathyroidal T3 production, and the Abstract identifies D2 as converting T4 to T3. Our copy does not establish that the thyroid is the sole source of T4 or explicitly state that it secretes some T3. (LLM, conf=0.85)
Experimental — accuracy not yet measuredLT4 acts essentially as a prodrug of T3 in target tissues, via the actions of the deiodinase enzymes.
“LT4 acts essentially as a prodrug of T3 in target tissues, via the actions of the deiodinase enzymes, described above”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [5]
T4 (or exogenous LT4) is converted to T3 locally in target tissues via the actions of three deiodinase enzymes, particularly Deiodinase 2.
“T4 (or exogenous LT4) is converted to T3 locally in target tissues, via the actions of three deiodinase enzymes, particularly Deiodinase 2”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [5]
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References 108 · Cited by 96
Research works printed but not linked: 3
- [88]Dentice M, Marsili A, Ambrosio R, Guardiola O, Sibilio A, Paik JH (2010) The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration. J Clin Invest 120(11): 4021– 4030 20978344 PMC2964991
- [90]Baqui M, Botero D, Gereben B, Curcio C, Harney JW, Salvatore D (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 12419801
- [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 18212764 PMC3133953
- Authors
- Bianco, A. C., & da Conceição, R. R.
- Affiliations
- Rush University Medical Center (US)
- Corresponding author
- Bianco, Antonio C.
- ORCID
- Bianco, Antonio C.
- Venue
- Methods in Molecular Biology
- Publisher
- Springer New York
- Published
- 2018
- Volume
- 1801
- Pages
- 67-83
- ISSN
- 1064-3745 (ISSN-L)
- 1940-6029
- PMC
- PMC6668716
- OpenAlex
- W2807809603
- Cited by
- 96
- References
- 108
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 12 · 2023: 13 · 2022: 17 · 2021: 16 · 2020: 11 · 2019: 2
- FWCI
- 42.87
- Type
- book chapter
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Methods in molecular biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058538)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- thyroid hormone signaling, thyroid hormone deiodinases, type 2 deiodinase, type 3 deiodinase, type I deiodinase, triiodothyronine, thyroxine, selenoproteins, thyroid hormone homeostasis, transcriptional regulation
- MeSH terms
- Animals, Disease Susceptibility, Humans, Hypothalamo-Hypophyseal System, Iodide Peroxidase, Thyroid Gland, Thyroid Hormones, Signal Transduction, Ubiquitination, Endoplasmic Reticulum Stress
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