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Selective Proteolysis of Human Type 2 Deiodinase: A Novel Ubiquitin-Proteasomal Mediated Mechanism for Regulation of Hormone Activation
Open accessAbstract
We investigated the mechanism by which T4 regulates its activation to T3 by the type 2 iodothyronine deiodinase (D2). D2 is a short- lived (t1/2 50 min), 31-kDa endoplasmic reticulum (ER) integral membrane selenoenzyme that generates intracellular T3. Inhibition of the ubiquitin (Ub) activating enzyme, E1, or MG132, a proteasome blocker, inhibits both the basal and substrate-induced acceleration of D2 degradation. Using a catalytically active transiently expressed FLAG-tagged-NH2-D2, we found rapid synthesis of high molecular mass (100-300 kDa) Ub-D2 conjugates that are catalytically inactive. Ub-D2 increases when cells are exposed to D2 substrate or MG132 and disappears rapidly after E1 inactivation. Fusion of FLAG epitope to the COOH terminus of D2 prolongs its half-life approximately 2.5-fold and increases the levels of active and, especially, Ub-D2. This indicates that COOH-terminal modification interferes with proteasomal uptake of Ub-D2 that can then be deubiquitinated. Interestingly, the type 1 deiodinase, a related selenoenzyme that also converts T4 to T3 but with a half-life of >12 h, is inactivated but not ubiquitinated or degraded after exposure to substrate. Thus, ubiquitination of the ER-resident enzyme D2 constitutes a specific posttranslational mechanism for T4 regulation of its own activation in the central nervous system and pituitary tissues in which D2-catalyzed T4 to T3 conversion is the major source of intracellular T3.
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“T4 induces ubiquitination and proteasomal degradation of D2, limiting T3 production via this pathway (45).”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [45]
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“T4 and rT3 also inhibit DIO2 by promoting its ubiquitination, which inhibits DIO2 activity and targets it for proteasomal degradation (37–40), forming an incoherent feedforward motif with T3 as the output.”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [38]
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“It has been shown that D2 protein levels and activity are regulated by post-translational mechanisms, especially ubiquitination (Gereben et al. 2000), which appears to be induced mainly by T4.”
From Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid-sensitive tissues (2014) · cites this paper as Gereben et al. 2000
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Metadata
- Authors
- Gereben, B., Goncalves, C., Harney, J. W., Larsen, P. R., & Bianco, A. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Bianco, Antonio C.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2000-11
- Volume
- 14
- Issue
- 11
- Pages
- 1697-1708
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2055205764
- Cited by
- 161
- References
- 26
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 7 · 2023: 7 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 11 · 2013: 6 · 2012: 7
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Universidade de São Paulo
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK036256, R01-DK-36256)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- type 2 deiodinase, selective proteolysis, ubiquitin-proteasome system, T4 to T3 conversion, selenoenzymes, endoplasmic reticulum, ubiquitination, deubiquitination, protein degradation, type I deiodinase
- MeSH terms
- Iodothyronine Deiodinase Type II, Animals, Epitopes, Base Sequence, Cell Line, Cysteine Endopeptidases, Endoplasmic Reticulum, Hormones, Humans, Iodide Peroxidase, Ligases, Molecular Sequence Data, Multienzyme Complexes, Oligopeptides, Peptides, Protein Processing, Post-Translational, Recombinant Proteins, Thyroxine, Triiodothyronine, Ubiquitins, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex
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