Protein tyrosine phosphatase 1B deficiency potentiates PERK/eiF2α signaling in brown adipocytes

Ahmed Bettaieb, Kosuke Matsuo, Izumi Matsuo, Shuo Wang, Ramzi Melhem, Antonis E. Koromilas, Fawaz Haj

Research output: Contribution to journalArticle

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Abstract

Background: Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and body mass, and has been implicated in endoplasmic reticulum (ER) stress. Herein, we assess the role of PTP1B in ER stress in brown adipocytes, which are key regulators of thermogenesis and metabolic response. Methodology/Principal Findings: To determine the role of PTP1B in ER stress, we utilized brown adipose tissue (BAT) from mice with adipose-specific PTP1B deletion, and brown adipocytes deficient in PTP1B and reconstituted with PTP1B wild type (WT) or the substrate-trapping PTP1B D181A (D/A) mutant. PTP1B deficiency led to upregulation of PERK-eIF2α phosphorylation and IRE1α-XBP1 sub-arms of the unfolded protein response. In addition, PTP1B deficiency sensitized differentiated brown adipocytes to chemical-induced ER stress. Moreover, PERK activation and tyrosine phosphorylation were increased in BAT and adipocytes lacking PTP1B. Increased PERK activity resulted in the induction of eIF2α phosphorylation at Ser51 and better translatability of ATF4 mRNA in response to ER stress. At the molecular level, we demonstrate direct interaction between PTP1B and PERK and identify PERK Tyr615 as a mediator of this association. Conclusions: Collectively, the data demonstrate that PTP1B is a physiologically-relevant modulator of ER stress in brown adipocytes and that PTP1B deficiency modulates PERK-eIF2α phosphorylation and protein synthesis.

Original languageEnglish (US)
Article numbere34412
JournalPLoS One
Volume7
Issue number4
DOIs
StatePublished - Apr 3 2012

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Brown Adipocytes
protein-tyrosine-phosphatase
adipocytes
Endoplasmic Reticulum Stress
endoplasmic reticulum
Phosphorylation
phosphorylation
Brown Adipose Tissue
brown adipose tissue
Tissue
unfolded protein response
Unfolded Protein Response
Thermogenesis
heat production
Adipocytes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Protein tyrosine phosphatase 1B deficiency potentiates PERK/eiF2α signaling in brown adipocytes. / Bettaieb, Ahmed; Matsuo, Kosuke; Matsuo, Izumi; Wang, Shuo; Melhem, Ramzi; Koromilas, Antonis E.; Haj, Fawaz.

In: PLoS One, Vol. 7, No. 4, e34412, 03.04.2012.

Research output: Contribution to journalArticle

Bettaieb A, Matsuo K, Matsuo I, Wang S, Melhem R, Koromilas AE et al. Protein tyrosine phosphatase 1B deficiency potentiates PERK/eiF2α signaling in brown adipocytes. PLoS One. 2012 Apr 3;7(4). e34412. https://doi.org/10.1371/journal.pone.0034412
Bettaieb, Ahmed ; Matsuo, Kosuke ; Matsuo, Izumi ; Wang, Shuo ; Melhem, Ramzi ; Koromilas, Antonis E. ; Haj, Fawaz. / Protein tyrosine phosphatase 1B deficiency potentiates PERK/eiF2α signaling in brown adipocytes. In: PLoS One. 2012 ; Vol. 7, No. 4.
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abstract = "Background: Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and body mass, and has been implicated in endoplasmic reticulum (ER) stress. Herein, we assess the role of PTP1B in ER stress in brown adipocytes, which are key regulators of thermogenesis and metabolic response. Methodology/Principal Findings: To determine the role of PTP1B in ER stress, we utilized brown adipose tissue (BAT) from mice with adipose-specific PTP1B deletion, and brown adipocytes deficient in PTP1B and reconstituted with PTP1B wild type (WT) or the substrate-trapping PTP1B D181A (D/A) mutant. PTP1B deficiency led to upregulation of PERK-eIF2α phosphorylation and IRE1α-XBP1 sub-arms of the unfolded protein response. In addition, PTP1B deficiency sensitized differentiated brown adipocytes to chemical-induced ER stress. Moreover, PERK activation and tyrosine phosphorylation were increased in BAT and adipocytes lacking PTP1B. Increased PERK activity resulted in the induction of eIF2α phosphorylation at Ser51 and better translatability of ATF4 mRNA in response to ER stress. At the molecular level, we demonstrate direct interaction between PTP1B and PERK and identify PERK Tyr615 as a mediator of this association. Conclusions: Collectively, the data demonstrate that PTP1B is a physiologically-relevant modulator of ER stress in brown adipocytes and that PTP1B deficiency modulates PERK-eIF2α phosphorylation and protein synthesis.",
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