Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eiF2a-mediated decrease in type 2 deiodinase synthesis

Rafael Arrojo e Drigo, Tatiana L. Fonseca, Melany Castillo, Matthias A Salathe, Gordana Simovic, Petra Mohácsik, Balazs Gereben, Antonio C. Bianco

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Cells respond rapidly to endoplasmic reticulum (ER) stress by blocking protein translation, increasing protein folding capacity, and accelerating degradation of unfolded proteins via ubiquitination and ER-associated degradation pathways. The ER resident type 2 deiodinase (D2) is normally ubiquitinated and degraded in the proteasome, a pathway that is accelerated by enzyme catalysis of T 4 to T 3. To test whether D2 is normally processed through ER-associated degradation, ER stress was induced in cells that endogenously express D2 by exposure to thapsigargin or tunicamycin. In all cell models, D2 activity was rapidly lost, to as low as of 30% of control activity, without affecting D2 mRNA levels; loss of about 40% of D2 activity and protein was also seen in human embryonic kidney 293 cells transiently expressing D2. In primary human airway cells with ER stress resulting from cystic fibrosis, D2 activity was absent. The rapid ER stress-induced loss of D2 resulted in decreased intracellular D2-mediated T 3 production. ER stress-induced loss of D2 was prevented in the absence of T 4, by blocking the proteasome with MG-132 or by treatment with chemical chaperones. Notably, ER stress did not alter D2 activity half-life but rather decreased D2 synthesis as assessed by induction of D2 mRNA and by [ 35S]methionine labeling. Remarkably, ER-stressinduced loss in D2 activity is prevented in cells transiently expressing an inactive eukaryotic initiation factor 2, indicating that this pathway mediates the loss of D2 activity. In conclusion, D2 is selectively lost during ER stress due to an eukaryotic initiation factor 2-mediated decrease in D2 synthesis and sustained proteasomal degradation. This explains the lack of D2 activity in primary human airway cells with ER stress resulting from cystic fibrosis.

Original languageEnglish
Pages (from-to)2065-2075
Number of pages11
JournalMolecular Endocrinology
Volume25
Issue number12
DOIs
StatePublished - Dec 1 2011

Fingerprint

Iodide Peroxidase
Endoplasmic Reticulum Stress
Thyroid Hormones
Eukaryotic Initiation Factor-2
Endoplasmic Reticulum-Associated Degradation
Proteasome Endopeptidase Complex
Cystic Fibrosis
Endoplasmic Reticulum
Tunicamycin
Protein Unfolding
Messenger RNA
Thapsigargin
Ubiquitination
Protein Folding
Protein Biosynthesis
Heat-Shock Proteins
Catalysis
Methionine
Proteolysis
Half-Life

Keywords

  • Ligands
  • Thyroid hormone

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

e Drigo, R. A., Fonseca, T. L., Castillo, M., Salathe, M. A., Simovic, G., Mohácsik, P., ... Bianco, A. C. (2011). Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eiF2a-mediated decrease in type 2 deiodinase synthesis. Molecular Endocrinology, 25(12), 2065-2075. https://doi.org/10.1210/me.2011-1061

Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eiF2a-mediated decrease in type 2 deiodinase synthesis. / e Drigo, Rafael Arrojo; Fonseca, Tatiana L.; Castillo, Melany; Salathe, Matthias A; Simovic, Gordana; Mohácsik, Petra; Gereben, Balazs; Bianco, Antonio C.

In: Molecular Endocrinology, Vol. 25, No. 12, 01.12.2011, p. 2065-2075.

Research output: Contribution to journalArticle

e Drigo, RA, Fonseca, TL, Castillo, M, Salathe, MA, Simovic, G, Mohácsik, P, Gereben, B & Bianco, AC 2011, 'Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eiF2a-mediated decrease in type 2 deiodinase synthesis', Molecular Endocrinology, vol. 25, no. 12, pp. 2065-2075. https://doi.org/10.1210/me.2011-1061
e Drigo, Rafael Arrojo ; Fonseca, Tatiana L. ; Castillo, Melany ; Salathe, Matthias A ; Simovic, Gordana ; Mohácsik, Petra ; Gereben, Balazs ; Bianco, Antonio C. / Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eiF2a-mediated decrease in type 2 deiodinase synthesis. In: Molecular Endocrinology. 2011 ; Vol. 25, No. 12. pp. 2065-2075.
@article{2bad38b1d4d6490fa4f73a8ca7e8bc62,
title = "Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eiF2a-mediated decrease in type 2 deiodinase synthesis",
abstract = "Cells respond rapidly to endoplasmic reticulum (ER) stress by blocking protein translation, increasing protein folding capacity, and accelerating degradation of unfolded proteins via ubiquitination and ER-associated degradation pathways. The ER resident type 2 deiodinase (D2) is normally ubiquitinated and degraded in the proteasome, a pathway that is accelerated by enzyme catalysis of T 4 to T 3. To test whether D2 is normally processed through ER-associated degradation, ER stress was induced in cells that endogenously express D2 by exposure to thapsigargin or tunicamycin. In all cell models, D2 activity was rapidly lost, to as low as of 30{\%} of control activity, without affecting D2 mRNA levels; loss of about 40{\%} of D2 activity and protein was also seen in human embryonic kidney 293 cells transiently expressing D2. In primary human airway cells with ER stress resulting from cystic fibrosis, D2 activity was absent. The rapid ER stress-induced loss of D2 resulted in decreased intracellular D2-mediated T 3 production. ER stress-induced loss of D2 was prevented in the absence of T 4, by blocking the proteasome with MG-132 or by treatment with chemical chaperones. Notably, ER stress did not alter D2 activity half-life but rather decreased D2 synthesis as assessed by induction of D2 mRNA and by [ 35S]methionine labeling. Remarkably, ER-stressinduced loss in D2 activity is prevented in cells transiently expressing an inactive eukaryotic initiation factor 2, indicating that this pathway mediates the loss of D2 activity. In conclusion, D2 is selectively lost during ER stress due to an eukaryotic initiation factor 2-mediated decrease in D2 synthesis and sustained proteasomal degradation. This explains the lack of D2 activity in primary human airway cells with ER stress resulting from cystic fibrosis.",
keywords = "Ligands, Thyroid hormone",
author = "{e Drigo}, {Rafael Arrojo} and Fonseca, {Tatiana L.} and Melany Castillo and Salathe, {Matthias A} and Gordana Simovic and Petra Moh{\'a}csik and Balazs Gereben and Bianco, {Antonio C.}",
year = "2011",
month = "12",
day = "1",
doi = "10.1210/me.2011-1061",
language = "English",
volume = "25",
pages = "2065--2075",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "12",

}

TY - JOUR

T1 - Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eiF2a-mediated decrease in type 2 deiodinase synthesis

AU - e Drigo, Rafael Arrojo

AU - Fonseca, Tatiana L.

AU - Castillo, Melany

AU - Salathe, Matthias A

AU - Simovic, Gordana

AU - Mohácsik, Petra

AU - Gereben, Balazs

AU - Bianco, Antonio C.

PY - 2011/12/1

Y1 - 2011/12/1

N2 - Cells respond rapidly to endoplasmic reticulum (ER) stress by blocking protein translation, increasing protein folding capacity, and accelerating degradation of unfolded proteins via ubiquitination and ER-associated degradation pathways. The ER resident type 2 deiodinase (D2) is normally ubiquitinated and degraded in the proteasome, a pathway that is accelerated by enzyme catalysis of T 4 to T 3. To test whether D2 is normally processed through ER-associated degradation, ER stress was induced in cells that endogenously express D2 by exposure to thapsigargin or tunicamycin. In all cell models, D2 activity was rapidly lost, to as low as of 30% of control activity, without affecting D2 mRNA levels; loss of about 40% of D2 activity and protein was also seen in human embryonic kidney 293 cells transiently expressing D2. In primary human airway cells with ER stress resulting from cystic fibrosis, D2 activity was absent. The rapid ER stress-induced loss of D2 resulted in decreased intracellular D2-mediated T 3 production. ER stress-induced loss of D2 was prevented in the absence of T 4, by blocking the proteasome with MG-132 or by treatment with chemical chaperones. Notably, ER stress did not alter D2 activity half-life but rather decreased D2 synthesis as assessed by induction of D2 mRNA and by [ 35S]methionine labeling. Remarkably, ER-stressinduced loss in D2 activity is prevented in cells transiently expressing an inactive eukaryotic initiation factor 2, indicating that this pathway mediates the loss of D2 activity. In conclusion, D2 is selectively lost during ER stress due to an eukaryotic initiation factor 2-mediated decrease in D2 synthesis and sustained proteasomal degradation. This explains the lack of D2 activity in primary human airway cells with ER stress resulting from cystic fibrosis.

AB - Cells respond rapidly to endoplasmic reticulum (ER) stress by blocking protein translation, increasing protein folding capacity, and accelerating degradation of unfolded proteins via ubiquitination and ER-associated degradation pathways. The ER resident type 2 deiodinase (D2) is normally ubiquitinated and degraded in the proteasome, a pathway that is accelerated by enzyme catalysis of T 4 to T 3. To test whether D2 is normally processed through ER-associated degradation, ER stress was induced in cells that endogenously express D2 by exposure to thapsigargin or tunicamycin. In all cell models, D2 activity was rapidly lost, to as low as of 30% of control activity, without affecting D2 mRNA levels; loss of about 40% of D2 activity and protein was also seen in human embryonic kidney 293 cells transiently expressing D2. In primary human airway cells with ER stress resulting from cystic fibrosis, D2 activity was absent. The rapid ER stress-induced loss of D2 resulted in decreased intracellular D2-mediated T 3 production. ER stress-induced loss of D2 was prevented in the absence of T 4, by blocking the proteasome with MG-132 or by treatment with chemical chaperones. Notably, ER stress did not alter D2 activity half-life but rather decreased D2 synthesis as assessed by induction of D2 mRNA and by [ 35S]methionine labeling. Remarkably, ER-stressinduced loss in D2 activity is prevented in cells transiently expressing an inactive eukaryotic initiation factor 2, indicating that this pathway mediates the loss of D2 activity. In conclusion, D2 is selectively lost during ER stress due to an eukaryotic initiation factor 2-mediated decrease in D2 synthesis and sustained proteasomal degradation. This explains the lack of D2 activity in primary human airway cells with ER stress resulting from cystic fibrosis.

KW - Ligands

KW - Thyroid hormone

UR - http://www.scopus.com/inward/record.url?scp=82055194436&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=82055194436&partnerID=8YFLogxK

U2 - 10.1210/me.2011-1061

DO - 10.1210/me.2011-1061

M3 - Article

VL - 25

SP - 2065

EP - 2075

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 12

ER -