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Targeting the unfolded protein response in disease

Key Points

  • The endoplasmic reticulum (ER) is the main organelle involved in protein folding, and different perturbations to its function lead to the accumulation of unfolded proteins, a condition known as ER stress.

  • The unfolded protein response (UPR) is a signal transduction pathway that mediates adaption to ER stress. Chronic ER stress triggers apoptosis.

  • ER stress is an emerging feature of many diseases, including cancer, neurodegeneration, diabetes and inflammatory diseases.

  • Small molecules that inhibit proximal UPR signalling components have proven efficacy in preclinical models of cancer.

  • Compounds that decrease the load of misfolded proteins at the ER have protective effects in models of ischaemia, neurodegeneration and diabetes.

  • Targeting the UPR pathway systemically may have undesired side effects in the long term.

  • Gene therapy is emerging as a valid strategy to locally manipulate ER stress levels in a disease context, with more clear applications on brain pathology.

  • Genetic manipulation of the UPR in mice revealed that the UPR has important physiological activities in processes that may not be directly related to ER stress, including cell differentiation, lipid and cholesterol metabolism, and inflammatory responses.

  • More studies are needed to identify the mechanisms that fine-tune the UPR. Moreover, predicting and defining the possible side effects of manipulating the UPR at the systemic level are needed for the validation of the pathway as a drug target and the progression of UPR modulators into clinical trials.

Abstract

Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a feature of specialized secretory cells and is also observed in many diseases, including cancer, diabetes, autoimmune conditions, liver disorders, obesity and neurodegenerative disorders. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response, which is an integrated signal transduction pathway that modulates many aspects of ER physiology. When these mechanisms of adaptation are insufficient to handle the unfolded protein load, cells undergo apoptosis. Here, we discuss recent advances in the design of novel compounds and therapeutic strategies to manipulate levels of ER stress in disease.

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Figure 1: The unfolded protein response.
Figure 2: Pharmacological modulation of IRE1.
Figure 3: Pharmacological modulation of PERK signalling.
Figure 4: Therapeutic molecules to target ER proteostasis.
Figure 5: Sites of action of therapeutic molecules to target ER proteostasis.

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Acknowledgements

The authors apologize to all their colleagues whose work could not be cited owing to space limitations. The authors thank J. Patterson for helpful discussions about IRE1 inhibitors, and U. Woehlbier and H. Urra for initial designs of the figures. This work was funded by the following grants and associations: FONDECYT 1100176; Millennium Institute No. P09-015-F; Ring Initiative ACT1109; FONDEF D11I1007; the ALS Therapy Alliance; the Muscular Dystrophy Association; the Michael J. Fox Foundation; the Alzheimer's Disease Association (to C.H.); the Institut National de la Santé et la Recherche Médicale (INSERM); the Institut National du Cancer, France; the Ligue contre le cancer, France; and Wellcome Trust Grant 084812/Z/08/Z (to H.P.H.).

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FURTHER INFORMATION

RCSB Protein Data Bank (PDB)

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Glossary

Secretory pathway

The cell infrastructure dedicated to the folding, maturation and trafficking of transmembrane and secreted proteins.

ER-associated protein degradation

(ERAD). A mechanism to eliminate misfolded proteins generated at the endoplasmic reticulum (ER) through their retrotranslocation to the cytosol and further degradation by the proteasome.

UPRosome

A signalling platform assembled at the level of IRE1 that modulates it activity and controls downstream effector responses.

Chaperone addiction

The dependency of a tumour cell on high chaperone levels and activities to cope with metabolic and environmental demands. This provides the tumour cells with a survival advantage which, when inhibited, might become toxic.

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Hetz, C., Chevet, E. & Harding, H. Targeting the unfolded protein response in disease. Nat Rev Drug Discov 12, 703–719 (2013). https://doi.org/10.1038/nrd3976

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