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Title: Involvement of the Nrf2-proteasome pathway in the endoplasmic reticulum stress response in pancreatic β-cells

Abstract

The ubiquitin-proteasome system plays a central role in protein quality control through endoplasmic reticulum (ER)-associated degradation (ERAD) of unfolded and misfolded proteins. NF-E2‐related factor 2 (Nrf2) is a transcription factor that controls the expression of an array of phase II detoxification and antioxidant genes. Nrf2 signaling has additionally been shown to upregulate the expression of the proteasome catalytic subunits in several cell types. Here, we investigated the role of Nrf2 in tunicamycin-induced ER stress using a murine insulinoma β-cell line, βTC-6. shRNA-mediated silencing of Nrf2 expression in βTC-6 cells significantly increased tunicamycin-induced cytotoxicity, elevated the expression of the pro-apoptotic ER stress marker Chop10, and inhibited tunicamycin-inducible expression of the proteasomal catalytic subunits Psmb5 and Psmb6. The effects of 3H-1,2-dithiole-3-thione (D3T), a small molecule Nrf2 activator, on ER stress were also examined in βTC-6 cells. D3T pretreatment reduced tunicamycin cytotoxicity and attenuated the tunicamycin-inducible Chop10 and protein kinase RNA-activated‐like ER kinase (Perk). The protective effect of D3T was shown to be associated with increased ERAD. D3T increased the expression of Psmb5 and Psmb6 and elevated chymotrypsin-like peptidase activity; proteasome inhibitor treatment blocked D3T effects on tunicamycin cytotoxicity and ER stress marker changes. Similarly, silencing of Nrf2 abolished the protective effect ofmore » D3T against ER stress. These results indicate that the Nrf2 pathway contributes to the ER stress response in pancreatic β-cells by enhancing proteasome-mediated ERAD. -- Highlights: ► Nrf2 silencing in pancreatic β-cells enhanced tunicamycin-mediated ER stress. ► Expression of the proteasome was inducible by Nrf2 signaling. ► Nrf2 activator D3T protected β-cells from tunicamycin-mediated ER stress. ► Protective effect of D3T was associated with Nrf2-dependent proteasome induction.« less

Authors:
;  [1]; ;  [2];  [3];  [2]
  1. Yeungnam University, College of Pharmacy, Gyeongsan-si, Gyeongsangbuk-do 712‐749 (Korea, Republic of)
  2. The Catholic University of Korea, College of Pharmacy, Wonmi-gu, Bucheon, Gyeonggi-do 420‐743 (Korea, Republic of)
  3. Inha University, College of Medicine, 253 Yonghyun-dong, Nam-gu, Incheon 402‐751 (Korea, Republic of)
Publication Date:
OSTI Identifier:
22215964
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 264; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; BENZOQUINONES; BROMIDES; CHYMOTRYPSIN; CYSTEINE; DETOXIFICATION; ENDOPLASMIC RETICULUM; GLUTATHIONE; LIGASES; PANCREAS; QUALITY CONTROL; RNA; TOXICITY; TRANSCRIPTION FACTORS

Citation Formats

Lee, Sanghwan, Hur, Eu-gene, Ryoo, In-geun, Jung, Kyeong-Ah, Kwak, Jiyeon, and Kwak, Mi-Kyoung, E-mail: mkwak@catholic.ac.kr. Involvement of the Nrf2-proteasome pathway in the endoplasmic reticulum stress response in pancreatic β-cells. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.08.021.
Lee, Sanghwan, Hur, Eu-gene, Ryoo, In-geun, Jung, Kyeong-Ah, Kwak, Jiyeon, & Kwak, Mi-Kyoung, E-mail: mkwak@catholic.ac.kr. Involvement of the Nrf2-proteasome pathway in the endoplasmic reticulum stress response in pancreatic β-cells. United States. doi:10.1016/J.TAAP.2012.08.021.
Lee, Sanghwan, Hur, Eu-gene, Ryoo, In-geun, Jung, Kyeong-Ah, Kwak, Jiyeon, and Kwak, Mi-Kyoung, E-mail: mkwak@catholic.ac.kr. Thu . "Involvement of the Nrf2-proteasome pathway in the endoplasmic reticulum stress response in pancreatic β-cells". United States. doi:10.1016/J.TAAP.2012.08.021.
@article{osti_22215964,
title = {Involvement of the Nrf2-proteasome pathway in the endoplasmic reticulum stress response in pancreatic β-cells},
author = {Lee, Sanghwan and Hur, Eu-gene and Ryoo, In-geun and Jung, Kyeong-Ah and Kwak, Jiyeon and Kwak, Mi-Kyoung, E-mail: mkwak@catholic.ac.kr},
abstractNote = {The ubiquitin-proteasome system plays a central role in protein quality control through endoplasmic reticulum (ER)-associated degradation (ERAD) of unfolded and misfolded proteins. NF-E2‐related factor 2 (Nrf2) is a transcription factor that controls the expression of an array of phase II detoxification and antioxidant genes. Nrf2 signaling has additionally been shown to upregulate the expression of the proteasome catalytic subunits in several cell types. Here, we investigated the role of Nrf2 in tunicamycin-induced ER stress using a murine insulinoma β-cell line, βTC-6. shRNA-mediated silencing of Nrf2 expression in βTC-6 cells significantly increased tunicamycin-induced cytotoxicity, elevated the expression of the pro-apoptotic ER stress marker Chop10, and inhibited tunicamycin-inducible expression of the proteasomal catalytic subunits Psmb5 and Psmb6. The effects of 3H-1,2-dithiole-3-thione (D3T), a small molecule Nrf2 activator, on ER stress were also examined in βTC-6 cells. D3T pretreatment reduced tunicamycin cytotoxicity and attenuated the tunicamycin-inducible Chop10 and protein kinase RNA-activated‐like ER kinase (Perk). The protective effect of D3T was shown to be associated with increased ERAD. D3T increased the expression of Psmb5 and Psmb6 and elevated chymotrypsin-like peptidase activity; proteasome inhibitor treatment blocked D3T effects on tunicamycin cytotoxicity and ER stress marker changes. Similarly, silencing of Nrf2 abolished the protective effect of D3T against ER stress. These results indicate that the Nrf2 pathway contributes to the ER stress response in pancreatic β-cells by enhancing proteasome-mediated ERAD. -- Highlights: ► Nrf2 silencing in pancreatic β-cells enhanced tunicamycin-mediated ER stress. ► Expression of the proteasome was inducible by Nrf2 signaling. ► Nrf2 activator D3T protected β-cells from tunicamycin-mediated ER stress. ► Protective effect of D3T was associated with Nrf2-dependent proteasome induction.},
doi = {10.1016/J.TAAP.2012.08.021},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 264,
place = {United States},
year = {2012},
month = {11}
}