Involvement of the Nrf2-proteasome pathway in the endoplasmic reticulum stress response in pancreatic ¦Â-cells

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• 作者：Sanghwan Lee ; Eu-gene Hur ; In-geun Ryoo ; Kyeong-Ah Jung ; Jiyeon Kwak ; Mi-Kyoung Kwak
• 关键词：ER ; endoplasmic reticulum ; UPR ; unfolded protein response ; ERAD ; ER-associated degradation ; iNrf2 ; NRF2 knockdown ¦ÂTC-6 ; iSc ; nonspecific control ¦ÂTC-6 ; ARE ; antioxidant-response element ; GSH ; glutathione ; Nqo1 ; NAP(D)H ; quinone oxidoreductase-1 ; Gclc
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2012
• 出版时间：1 November, 2012
• 年：2012
• 卷：264
• 期：3
• 页码：431-438
• 全文大小：634 K

文摘

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 ¦Â-cell line, ¦ÂTC-6. shRNA-mediated silencing of Nrf2 expression in ¦ÂTC-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 ¦ÂTC-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 ¦Â-cells by enhancing proteasome-mediated ERAD.