Review
Coordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway

https://doi.org/10.1016/j.biocel.2005.09.018Get rights and content

Abstract

In the broadest sense, cellular stress describes conditions wherein cells encounter and react to a ‘non-normal’ state. Perturbations may originate through both extracellular and intracellular means. Whereas transient levels of stress are expected to occur on a regular basis, a series of checks and balances ensures that cells are well equipped to maintain a homeostatic state. In the case of supra-physiological stress signaling, cellular challenges are more severe, and programmed cell death may be the best option for the organism. The ability of a cell, and by extension, an organism, to adequately manage cellular stress is fundamental—a question of life or death. The endoplasmic reticulum (ER) is exquisitely poised to sense and respond to cellular stresses including those that result from metabolic and/or protein folding imbalances. In response to stress originating from within the ER, the PERK and Ire1 protein kinases, along with other proximal signaling molecules, initiate a program of transcriptional and translational regulation termed the unfolded protein response. A consequence of ER stress is the accumulation of reactive oxygen species that promotes a state of oxidative stress. PERK signaling, via activation of the Nrf2 and ATF4 transcription factors, coordinates the convergence of ER stress with oxidative stress signaling. Here we discuss progress regarding the signaling pathways involved in these cellular stresses and the implications of the intersection between the two signaling pathways.

Section snippets

Endoplasmic reticulum stress

In eukaryotic cells, the endoplasmic reticulum (ER) is the first organelle in the secretory pathway. As such, the ER serves as a site of secretory protein synthesis and modification prior to directing protein delivery to other secretory organelles. This process is highly regulated, consisting of chaperones, signaling molecules and a network of degradation machinery that maintain homeostasis (Schroder & Kaufman, 2005). Upon disruption in either protein folding or modification within the ER, a

The unfolded protein response

In mammalian cells, the proximal signaling events that occur in response to UPR activation involve the release of ER-resident signaling molecules, activating transcription factor 6 (ATF6), inositol requiring 1 (Ire1) and PKR-like endoplasmic reticulum kinase (PERK), from binding to the ER-resident chaperone, BIP/GRP78 resulting in their subsequent activation (Bertolotti, Zhang, Hendershot, Harding, & Ron, 2000; Haze, Yoshida, Yanagi, Yura, & Mori, 1999; Li et al., 2000, Ma et al., 2002a). As a

Oxidative stress

While the induction of the UPR results from stress emanating from one organelle, the broad response termed oxidative stress results from the coordination of hundreds of signaling molecules that reside in all cellular compartments (Hayes & Pulford, 1995). On a broad scale, oxidative stress results from the exposure of cells to ROS (Richter et al., 1995, Rushmore et al., 1991). ROS may originate during cellular metabolic processes such as oxidative phosphorylation within the mitochondria, or they

Nrf2/Keap1 signaling pathway

Nrf2 belongs to the Cap ‘n’ Collar (CNC) family of basic leucine zipper (bZip) transcription factors that includes NF-E2, Nrf1-3 and Bach1-2 (Andrews, Erdjument-Bromage, Davidson, Tempst, & Orkin, 1993; Chan, Han, & Kan, 1993; Kobayashi et al., 1999, Moi et al., 1994; Oyake et al., 1996). While NF-E2 is restricted to erythrocytes where it regulates globin-specific gene expression (Andrews et al., 1993), the related NF-E2 related factor (Nrf) proteins (Nrf1-3) are ubiquitously expressed and

Neurodegenerative diseases

The broad classification of neurodegenerative disorders encompasses a group of devastating diseases characterized by abnormal neuronal physiology coupled with a loss of neurological function. While the causative effects of this family of diseases are still being investigated, it is clear that alterations in protein folding and redox homeostasis are prominent features of the diseases (Andersen, 2004, Forman et al., 2003). Animal models and human autopsy results consistently reveal the

Outlook

A large body of work has established paradigms for both UPR and oxidative stress signaling, including mechanisms of regulation and modes of activity. We are just now beginning to appreciate the vast potential for these pathways in development and homeostatic control as well as disease prevention and progression. While the connection between ER stress and the subsequent induction of oxidative stress has been appreciated for several years, recent data have offered a mechanism for the intersection

Acknowledgments

We thank members of our laboratory for helpful discussions and support from NIH/NCI CA104838 (JAD).

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