PERK-dependent Activation of Nrf2 Contributes to Redox Homeostasis and Cell Survival following Endoplasmic Reticulum Stress*

By S. Cullinan, J. Diehl. Journal of Biological Chemistry, 2004

723 citations recorded by the source corpus.

The accumulation of unfolded proteins elicits a cellular response that triggers both pro-survival and pro-apoptotic signaling events. PERK-dependent activation of NF-E2-related factor-2 (Nrf2) is critical for survival signaling during this response; however, the mechanism whereby Nrf2 confers a protective advantage to stressed cells remains to be defined. We now demonstrate that Nrf2 activation contributes to the maintenance of glutathione levels, which in turn functions as a buffer for the accumulation of reactive oxygen species during the unfolded protein response. The deleterious effects of Nrf2 or PERK deficiencies could be attenuated by the restoration of cellular glutathione levels or Nrf2 activity. In addition, the inhibition of reactive oxygen species production attenuated apoptotic induction following endoplasmic reticulum stress. Our data suggest that perturbations in cellular redox status sensitize cells to the harmful effects of endoplasmic reticulum stress, but that other factors are essential for apoptotic commitment.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/387de3d3a16757ef50603117b8aeba8d29983121

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Citations in the corpus

Oxidative and Electrophilic Stresses Activate Nrf2 through Inhibition of Ubiquitination Activity of Keap1 (2006, background): “It has been reported that both endoplasmic reticulum stress-dependent kinase and protein kinase C phosphorylate Nrf2, resulting in the dissociation of Nrf2 from Keap1 (4, 5, 29).”
Induction of phase I, II and III drug metabolism/transport by xenobiotics (2005, background): “Furthermore, Cullinan et aL have indicated that Nrf2 is directly phosphorylated by PERK, a transmembrane transcription factor, following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) (Cullinan and Diehl, 2004; Cullinan et aL, 2003).”
Endoplasmic Reticulum Stress and Associated ROS (2016, background): “PERK phosphorylates eukaryotic initiation factor 2 (eIF2α) to reduce the GTP-bound form (initial phase of polypeptide synthesis) [21] and allow translation of ATF4, one of the UPR-dependent signaling proteins.”
Molecular Mechanisms of Nrf2-Mediated Antioxidant Response (2009, neutral): “thapthiagargen (calcium-releasing inhibitor) and glucose deprivation [118].”
The cytoprotective role of the Keap1–Nrf2 pathway (2011, background): “…Nrf2 has also been shown to be phosphorylated by GSK3b, PERK and CK2, suggesting that the regulation of Nrf2 has the potential to be very complex and could be fine-tuned by a number of different mechanisms (Salazar et al. 2006; Cullinan et al. 2003; Cullinan and Diehl 2004; Pi et al. 2007).”
ER stress-induced cell death mechanisms. (2013, background): “Contents lists available at ScienceDirect Biochimica et Biophysica Acta j ourna l homepage: www.e lsev ie r .com/ locate /bbamcr Review ER stress-induced cell death mechanisms☆ Renata Sano, John C. Reed ⁎ Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037, USA Abbreviations: AGE, advanc”
Cellular Stress Responses: Cell Survival and Cell Death (2010, background): “Moreover, perturbations in cellular redox status sensitize cells to the harmful effects of ER stress [199].”
The Endoplasmic Reticulum: Folding, Calcium Homeostasis, Signaling, and Redox Control (2006, neutral): “oxidative folding of proteins, the precise mechanisms that lead to the native structure of a disulfide bond-containing protein as well as the cellular components required are not yet understood in their entirety.”
Role of nrf2 in oxidative stress and toxicity. (2013, background): “PERK phosphorylates Nrf2 on Thr-80 to activate Nrf2 and induce ARE genes, which increase GSH level, reduce ROS in ER, and promote survival (67, 111) (Figure 3c).”
Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. (2018, background): “to compensate for high ROS levels, which are important mediators of inflammation (34, 38, 122).”