Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling

Rafael Arrojo E Drigo, Tatiana L. Fonseca, Joao Pedro Saar Werneck-De-Castro, Antonio C. Bianco

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Background: Thyroid hormone signaling is critical for development, growth and metabolic control in vertebrates. Although serum concentration of thyroid hormone is remarkable stable, deiodinases modulate thyroid hormone signaling on a time- and cell-specific fashion by controlling the activation and inactivation of thyroid hormone. Scope of the review: This review covers the recent advances in D2 biology, a member of the iodothyronine deiodinase family, thioredoxin fold-containing selenoenzymes that modify thyroid hormone signaling in a time- and cell-specific manner. Major conclusions: D2-catalyzed T3 production increases thyroid hormone signaling whereas blocking D2 activity or disruption of the Dio2 gene leads to a state of localized hypothyroidism. D2 expression is regulated by different developmental, metabolic or environmental cues such as the hedgehog pathway, the adrenergic- and the TGR5-activated cAMP pathway, by xenobiotic molecules such as flavonols and by stress in the endoplasmic reticulum, which specifically reduces de novo synthesis of D2 via an eIF2a-mediated mechanism. Thus, D2 plays a central role in important physiological processes such as determining T3 content in developing tissues and in the adult brain, and promoting adaptive thermogenesis in brown adipose tissue. Notably, D2 is critical in the T4-mediated negative feed-back at the pituitary and hypothalamic levels, whereby T4 inhibits TSH and TRH expression, respectively. Notably, ubiquitination is a major step in the control of D2 activity, whereby T4 binding to and/or T4 catalysis triggers D2 inactivation by ubiquitination that is mediated by the E3 ubiquitin ligases WSB-1 and/or TEB4. Ubiquitinated D2 can be either targeted to proteasomal degradation or reactivated by deubiquitination, a process that is mediated by the deubiquitinases USP20/33 and is important in adaptive thermogenesis. General significance: Here we review the recent advances in the understanding of D2 biology focusing on the mechanisms that regulate its expression and their biological significance in metabolically relevant tissues. This article is part of a Special Issue entitled Thyroid hormone signalling.

Original languageEnglish
Pages (from-to)3956-3964
Number of pages9
JournalBiochimica et Biophysica Acta - General Subjects
Volume1830
Issue number7
DOIs
StatePublished - Jul 1 2013

Fingerprint

Iodide Peroxidase
Thyroid Hormones
Thermogenesis
Ubiquitination
Tissue
Physiological Phenomena
Flavonols
Thioredoxins
Endoplasmic Reticulum Stress
Brown Adipose Tissue
Ubiquitin-Protein Ligases
Hedgehogs
Xenobiotics
Hypothyroidism
iodothyronine deiodinase type II
Catalysis
Growth and Development
Adrenergic Agents
Cues
Vertebrates

Keywords

  • Deiodinase
  • Metabolism
  • Selenoprotein
  • Thyroid hormone

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. / Arrojo E Drigo, Rafael; Fonseca, Tatiana L.; Werneck-De-Castro, Joao Pedro Saar; Bianco, Antonio C.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1830, No. 7, 01.07.2013, p. 3956-3964.

Research output: Contribution to journalArticle

Arrojo E Drigo, Rafael ; Fonseca, Tatiana L. ; Werneck-De-Castro, Joao Pedro Saar ; Bianco, Antonio C. / Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. In: Biochimica et Biophysica Acta - General Subjects. 2013 ; Vol. 1830, No. 7. pp. 3956-3964.
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