Type 2 iodothyronine deiodinase in rat pituitary tumor cells is inactivated in proteasomes
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The goal of these studies was to define the rate-limiting steps in the inactivation of type 2 iodothyronine deiodinase (D2).We examined the effects of ATP depletion, a lysosomal protease inhibitor, and an inhibitor of actin polymerization on D2 activity in the presence or absence of cycloheximide or 3,3 Ј ,5 Ј -triiodothyronine (reverse T3, rT3) in rat pituitary tumor cells (GH4C1).We also analyzed the effects of the proteasomal proteolysis inhibitor carbobenzoxy-L -leucyl-L -leucyl-L -leucinal (MG132).The half-life of D2 activity in hypothyroid cells was 47 min after cycloheximide and 60 min with rT3 (3 nM).rT3 and cycloheximide were additive, reducing D2 half-life to 20 min.D2 degradation was partially inhibited by ATP depletion, but not by cytochalasin B or chloroquine.Incubation with MG132 alone increased D2 activity by 30-40% for several hours, and completely blocked the cycloheximide-or rT3-induced decrease in D2 activity.These results suggest that D2 is inactivated by proteasomal uptake and that substrate reduces D2 activity by accelerating degradation through this pathway.This is the first demonstration of a critical role for proteasomes in the post-translational regulation of D2 activity.( J. Clin.Invest.1998.102:1895-1899 .) Key words: selenocysteine • thyroid hormone metabolism • reverse T3 • MG132 • selenium MethodsReagents.MG132 was obtained from the Peptide Institute, Inc. (Osaka, Japan) and dissolved in DMSO.CCCP, chloroquine, and cytochalasin B were from Sigma Chemical Co.(St.Louis, MO).Cycloheximide and rT3 were from Calbiochem (La Jolla, CA).CCCP was dissolved in 100% ethanol and cytochalasin B and cycloheximide in DMSO.rT3 was dissolved in 70% ethanol.Outer ring-labeled [ 125 I]-
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T4 and rT3 inhibit DIO2 by promoting its ubiquitination, which inhibits DIO2 activity and targets it for proteasomal degradation, forming an incoherent feedforward motif with T3 as the output.
“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 [37]
The Introduction identifies T4 and rT3 as D2 substrates that decrease its activity. The Results and Discussion show that rT3 accelerates D2 degradation through a proteasome-dependent pathway. The paper proposes ubiquitin conjugation as a possible step but does not demonstrate that T4 or rT3 promotes D2 ubiquitination. (LLM, conf=0.86)
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Cerebral cortex responds rapidly to thyroid hormones
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Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling1
Gereben, B., Zavacki, A. M., Ribich, S., Kim, B. W., Huang, S. A., Simonides, W. S., Zeöld, A., & Bianco, A. C. (2008) · Endocrine Reviews · doi:10.1210/er.2008-0019 · Cited by 891 · see citing works
Deiodinases: implications of the local control of thyroid hormone action
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Paradigms of dynamic control of thyroid hormone signaling
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Self-citationChristoffolete, M. A., Ribeiro, R., Singru, P., Fekete, C., da Silva, W. S., Gordon, D. F., Huang, S. A., Crescenzi, A., Harney, J. W., Ridgway, E. C., et al. (2006) · Endocrinology · doi:10.1210/en.2005-1300 · Cited by 118 · see citing works
Self-citationIntrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion
Jing, L., & Zhang, Q. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.992883 · Cited by 61 · see citing works
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- Authors
- Steinsapir, J., Harney, J., & Larsen, P. R.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Larsen, P R
- Venue
- Journal of Clinical Investigation
- Published
- 1998-12-01
- Volume
- 102
- Issue
- 11
- Pages
- 1895-1899
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC509140
- OpenAlex
- W2123790179
- Cited by
- 102
- References
- 3
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 4 · 2013: 4 · 2012: 5
- FWCI
- 2.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Endocrine Fellows Foundation
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK36256, R01DK036256)
- 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
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- type 2 deiodinase, proteasomal degradation, reverse T3, post-translational regulation, selenocysteine, thyroid hormone metabolism, pituitary tumor cells, GH4C1 cells, MG132, cycloheximide, ATP depletion, enzyme inactivation
- MeSH terms
- Iodothyronine Deiodinase Type II, Adenosine Triphosphate, Animals, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Chloroquine, Cycloheximide, Cysteine Endopeptidases, Cytochalasin B, Iodide Peroxidase, Isoenzymes, Leupeptins, Multienzyme Complexes, Neoplasm Proteins, Pituitary Neoplasms, Protease Inhibitors, Protein Synthesis Inhibitors, Thyroxine, Triiodothyronine, Reverse, Tumor Cells, Cultured, Ubiquitins, Proteasome Endopeptidase Complex, Rats
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