Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities

Key Points

  • Perturbations of the endoplasmic reticulum (ER) caused by accumulation of unfolded proteins in this organelle trigger signal-transduction responses that assist with restoration of homeostasis during short-term but contribute to pathology when prolonged, including causing cell death.

  • Among the stimuli that trigger ER stress are hypoxia, oxidative injury, a high-fat diet, hypoglycaemia, protein-inclusion bodies and viral infection, thus linking these organelle-initiated responses to a diversity of diseases, including cancer, autoimmunity, diabetes, heart disease, stroke and neurodegeneration.

  • With increasing recognition of ER stress in association with human diseases and with improving understanding of the underlying molecular mechanisms, novel targets for drug discovery and new strategies for therapeutic intervention are beginning to emerge from the study of ER stress.

  • Scenarios in which ER stress contributes to disease are outlined and prospects for drug discovery are discussed.

  • Among the cell death mechanisms addressed are: pro-apoptotic signals resulting from activation of the ER-associated kinase IRE1, an upstream activator of apoptotic signalling kinase 1 (ASK1) that activates a stress kinase pathway affecting the activity or expression of several apoptosis regulators including BCL-2, BIM and CHOP; cytoprotective ER-membrane-associated proteins that modulate ER stress signalling; and the interplay among ER-initiated signal-transduction mechanisms that control apoptosis, necrosis and autophagy.

Abstract

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathological conditions. These include hypoxia, oxidative injury, high-fat diet, hypoglycaemia, protein inclusion bodies and viral infection. ER stress triggers an evolutionarily conserved series of signal-transduction events, which constitutes the unfolded protein response. These signalling events aim to ameliorate the accumulation of unfolded proteins in the ER; however, when these events are severe or protracted they can induce cell death. With the increasing recognition of an association between ER stress and human diseases, and with the improved understanding of the diverse underlying molecular mechanisms, novel targets for drug discovery and new strategies for therapeutic intervention are beginning to emerge.

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Figure 1: UPR events and connection to the cell death machinery.
Figure 2: Calcium-induced pathways relevant to cell death and ER stress.

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Acknowledgements

We thank T. Siegfried for manuscript preparation, and the National Institutes of Health for generous support.

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Correspondence to John C. Reed.

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J.C.R. has served on the board of ISIS Pharmaceuticals.

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NCI protocol ID NCI-07-C-0047

Glossary

Molecular chaperone

A molecular chaperone is a protein that aids the folding of other proteins. Some molecular chaperones reside in the lumen of the endoplasmic reticulum, such as GRP78, a member of the HSP70 family, and GRP94, a member of the HSP90 family.

Protein disulphide isomerase

(PDI). A cellular enzyme in the lumen of the endoplasmic reticulum of eukaryotes or the periplasmic region of prokaryotes. This enzyme catalyses the formation and breakage of disulphide bonds between cysteine residues in proteins, which affects protein folding.

Unfolded protein response

(UPR). A conserved physiological response involving endoplasmic reticulum (ER)-initiated signal-transduction events, induced by accumulation of unfolded proteins in the lumen of the ER. In mammals, the UPR includes signals initiated by ER membrane-associated proteins: IRE1, PERK and ATF6.

ER stress

An organelle-initiated cell stress condition, typically associated with accumulation of misfolded or unfolded proteins in the lumen of the ER. ER stress is caused by a wide diversity of stimuli.

ER-assisted degradation

(ERAD). ERAD involves the retrograde translocation of unfolded proteins from the lumen of the ER to the cytosol, where ER membrane-associated ubiquitin ligases post-translationally modify the translocated proteins thereby targeting them for degradation, usually by the 26S proteasome.

Autophagy

Autophagy, or autophagocytosis, is a catabolic celullar process involving the lysosome-dependent degradation of macromolecules, organelles and other cell components. Autophagy plays housekeeping roles in protein degradation, complementing the proteasome-based protein degradation system. Autophagy can also be important for cell survival during times of nutrient deprivation and hypoxia, and is induced in some cases by endoplasmic reticulum stress. Autophagy has also been associated with cell death in some contexts.

EIF2α

(Eukaryotic translation initiation factor 2α). The translation initiation complex EIF2 is a heterotrimer of EIF2α, EIF2β and EIF2γ. This complex binds to GTP and Met-tRNA. It transfers Met-tRNA to the 40S subunit of the ribosome to form the 43S pre-initiation complex. Successive rounds of translation and initiation are promoted by exchanging GDP for GTP. Phosphorylation of EIF2α by PERK inactivates EIF2α, resulting in inhibition of cap-dependent translation initiation.

S-nitrosylation

S-nitrosylation describes the covalent attachment of a nitrogen monoxide group to the thiol (-SH) of cysteines in proteins. It is a post-translational modification of proteins that can modulate cellular signalling, which provides a mechanism for redox-based physiological regulation.

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Kim, I., Xu, W. & Reed, J. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7, 1013–1030 (2008). https://doi.org/10.1038/nrd2755

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