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

Brian W. Kim, Ann M. Zavacki, Cyntia Curcio-Morelli, Monica Dentice, John W. Harney, P. Reed Larsen, Antonio C. Bianco

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

The type 2 iodothyronine selenodeiodinase (D2) is an endoplasmic reticulum (ER)-resident selenoprotein that activates T 4 to T 3, playing a critical role in thyroid homeostasis. D2 has an approximately 45-min half-life due to selective ubiquitin-mediated ER-associated degradation (ERAD), a process of particular interest because it is accelerated by exposure t o D2 substrates, T 4 or rT 3. The present in vitro binding studies indicate that glutathione-S-transferase (GST)-human D2 fusion proteins specifically associate with a mammalian homolog of the ubiquitin conjugase UBC7 (MmUBC7), with localization to amino acids 169-234 of D2. Coexpression of D2 with an inactive D2 mutant or a truncated version containing amino acids 169-234 stabilizes D2 half-life, supporting the importance of the carboxyl region of D2 for ERAD. Mammalian UBC6 (MmUBC6) does not directly associate with D2 but can associate with a complex containing UBC7 and D2. At the same time, functional studies in human embryonic kidney-293 cells indicate that D2 activity half-life and protein levels are stabilized only when inactive mutants of both UBC6 and UBC7 are overexpressed with D2, suggesting that redundancy may exist at the level of the E2 for both basal and substrate-accelerated D2 ERAD. In conclusion, D2 ERAD in human cells proceeds via an association between UBC7 and the carboxyl region of D2, a unique mechanism for the control of thyroid hormone activation.

Original languageEnglish
Pages (from-to)2603-2612
Number of pages10
JournalMolecular Endocrinology
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2003

Fingerprint

Endoplasmic Reticulum-Associated Degradation
Iodide Peroxidase
Half-Life
Ubiquitin
gamma-Glutamyl Hydrolase
Selenoproteins
Amino Acids
Glutathione Transferase
Thyroid Hormones
Endoplasmic Reticulum
Thyroid Gland
Homeostasis
Kidney
iodothyronine deiodinase type II
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Kim, Brian W.; Zavacki, Ann M.; Curcio-Morelli, Cyntia; Dentice, Monica; Harney, John W.; Larsen, P. Reed; Bianco, Antonio C.

In: Molecular Endocrinology, Vol. 17, No. 12, 01.12.2003, p. 2603-2612.

Research output: Contribution to journalArticle

Kim, Brian W. ; Zavacki, Ann M. ; Curcio-Morelli, Cyntia ; Dentice, Monica ; Harney, John W. ; Larsen, P. Reed ; Bianco, Antonio C. / 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. In: Molecular Endocrinology. 2003 ; Vol. 17, No. 12. pp. 2603-2612.
@article{9f9b3e0e239a43ca96e2a551f8c32bdf,
title = "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",
abstract = "The type 2 iodothyronine selenodeiodinase (D2) is an endoplasmic reticulum (ER)-resident selenoprotein that activates T 4 to T 3, playing a critical role in thyroid homeostasis. D2 has an approximately 45-min half-life due to selective ubiquitin-mediated ER-associated degradation (ERAD), a process of particular interest because it is accelerated by exposure t o D2 substrates, T 4 or rT 3. The present in vitro binding studies indicate that glutathione-S-transferase (GST)-human D2 fusion proteins specifically associate with a mammalian homolog of the ubiquitin conjugase UBC7 (MmUBC7), with localization to amino acids 169-234 of D2. Coexpression of D2 with an inactive D2 mutant or a truncated version containing amino acids 169-234 stabilizes D2 half-life, supporting the importance of the carboxyl region of D2 for ERAD. Mammalian UBC6 (MmUBC6) does not directly associate with D2 but can associate with a complex containing UBC7 and D2. At the same time, functional studies in human embryonic kidney-293 cells indicate that D2 activity half-life and protein levels are stabilized only when inactive mutants of both UBC6 and UBC7 are overexpressed with D2, suggesting that redundancy may exist at the level of the E2 for both basal and substrate-accelerated D2 ERAD. In conclusion, D2 ERAD in human cells proceeds via an association between UBC7 and the carboxyl region of D2, a unique mechanism for the control of thyroid hormone activation.",
author = "Kim, {Brian W.} and Zavacki, {Ann M.} and Cyntia Curcio-Morelli and Monica Dentice and Harney, {John W.} and Larsen, {P. Reed} and Bianco, {Antonio C.}",
year = "2003",
month = "12",
day = "1",
doi = "10.1210/me.2003-0082",
language = "English",
volume = "17",
pages = "2603--2612",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "12",

}

TY - JOUR

T1 - 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

AU - Kim, Brian W.

AU - Zavacki, Ann M.

AU - Curcio-Morelli, Cyntia

AU - Dentice, Monica

AU - Harney, John W.

AU - Larsen, P. Reed

AU - Bianco, Antonio C.

PY - 2003/12/1

Y1 - 2003/12/1

N2 - The type 2 iodothyronine selenodeiodinase (D2) is an endoplasmic reticulum (ER)-resident selenoprotein that activates T 4 to T 3, playing a critical role in thyroid homeostasis. D2 has an approximately 45-min half-life due to selective ubiquitin-mediated ER-associated degradation (ERAD), a process of particular interest because it is accelerated by exposure t o D2 substrates, T 4 or rT 3. The present in vitro binding studies indicate that glutathione-S-transferase (GST)-human D2 fusion proteins specifically associate with a mammalian homolog of the ubiquitin conjugase UBC7 (MmUBC7), with localization to amino acids 169-234 of D2. Coexpression of D2 with an inactive D2 mutant or a truncated version containing amino acids 169-234 stabilizes D2 half-life, supporting the importance of the carboxyl region of D2 for ERAD. Mammalian UBC6 (MmUBC6) does not directly associate with D2 but can associate with a complex containing UBC7 and D2. At the same time, functional studies in human embryonic kidney-293 cells indicate that D2 activity half-life and protein levels are stabilized only when inactive mutants of both UBC6 and UBC7 are overexpressed with D2, suggesting that redundancy may exist at the level of the E2 for both basal and substrate-accelerated D2 ERAD. In conclusion, D2 ERAD in human cells proceeds via an association between UBC7 and the carboxyl region of D2, a unique mechanism for the control of thyroid hormone activation.

AB - The type 2 iodothyronine selenodeiodinase (D2) is an endoplasmic reticulum (ER)-resident selenoprotein that activates T 4 to T 3, playing a critical role in thyroid homeostasis. D2 has an approximately 45-min half-life due to selective ubiquitin-mediated ER-associated degradation (ERAD), a process of particular interest because it is accelerated by exposure t o D2 substrates, T 4 or rT 3. The present in vitro binding studies indicate that glutathione-S-transferase (GST)-human D2 fusion proteins specifically associate with a mammalian homolog of the ubiquitin conjugase UBC7 (MmUBC7), with localization to amino acids 169-234 of D2. Coexpression of D2 with an inactive D2 mutant or a truncated version containing amino acids 169-234 stabilizes D2 half-life, supporting the importance of the carboxyl region of D2 for ERAD. Mammalian UBC6 (MmUBC6) does not directly associate with D2 but can associate with a complex containing UBC7 and D2. At the same time, functional studies in human embryonic kidney-293 cells indicate that D2 activity half-life and protein levels are stabilized only when inactive mutants of both UBC6 and UBC7 are overexpressed with D2, suggesting that redundancy may exist at the level of the E2 for both basal and substrate-accelerated D2 ERAD. In conclusion, D2 ERAD in human cells proceeds via an association between UBC7 and the carboxyl region of D2, a unique mechanism for the control of thyroid hormone activation.

UR - http://www.scopus.com/inward/record.url?scp=0347480259&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0347480259&partnerID=8YFLogxK

U2 - 10.1210/me.2003-0082

DO - 10.1210/me.2003-0082

M3 - Article

VL - 17

SP - 2603

EP - 2612

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 12

ER -