Abstract
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress, resulting in activation of the unfolded protein response (UPR) that aims to restore protein homeostasis. However, the UPR also plays an important pathological role in many diseases, including metabolic disorders, cancer and neurological disorders. Over the last decade, significant effort has been invested in targeting signalling proteins involved in the UPR and an array of drug-like molecules is now available. However, these molecules have limitations, the understanding of which is crucial for their development into therapies. Here, we critically review the existing ER stress and UPR-directed drug-like molecules, highlighting both their value and their limitations.
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Acknowledgements
S.J.M. and J.E.C. are supported by the Medical Research Council (MRC) (MR/V028669/1, MR/R009120/1), the Engineering and Physical Sciences Research Council (EPSRC) (EP/R03558X/1), the British Lung Foundation (BLF) (MEDPG21F\4), the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014), Royal Papworth Hospital and the Alpha1-Foundation (pC ID: 830153, pC ID: 614939). D.R. is supported by a Wellcome Trust Principal Research Fellowship (Wellcome 200848/Z/16/Z). All authors benefit from a Wellcome Trust Strategic Award to the Cambridge Institute for Medical Research (Wellcome 100140).
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Glossary
- ER stress
-
A toxic state that occurs when unfolded or incompletely folded proteins accumulate in the endoplasmic reticulum (ER).
- Unfolded protein response
-
(UPR). A cellular signalling pathway triggered by endoplasmic reticulum (ER) dysfunction and comprising three distinct arms downstream of the ER stress sensors inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6) and protein kinase RNA-like endoplasmic reticulum kinase (PERK).
- Inositol-requiring enzyme 1
-
(IRE1). An endoplasmic reticulum (ER) stress sensor possessing auto-kinase and endonuclease activities that participates in splicing XBP1 mRNA and in the degradation of mRNAs via regulated IRE1-dependent decay (RIDD).
- Activating transcription factor 6
-
(ATF6). An endoplasmic reticulum (ER) stress sensor that is proteolytically cleaved to generate a soluble transcription factor.
- Protein kinase RNA-like endoplasmic reticulum kinase
-
(PERK). An endoplasmic reticulum (ER) stress sensor that selectively phosphorylates eukaryotic initiation factor 2α (eIF2α) to trigger the integrated stress response (ISR).
- PPP1R15A
-
A protein phosphatase 1 (PP1) regulatory subunit that selectively dephosphorylates eukaryotic initiation factor 2α (eIF2α): PPP1R15A is induced during the integrated stress response (ISR), whereas PPP1R15B is constitutively expressed.
- XBP1
-
A transcription factor induced when inositol-requiring enzyme 1 (IRE1) initiates splicing of XBP1 mRNA.
- Pharmacological chaperones
-
Chemical chaperones that facilitate the correct folding of a specific target protein.
- Chemical chaperone
-
A small molecule that facilitates correct protein folding.
- Molecular chaperone
-
A protein that facilitates the correct folding of other proteins.
- ER-associated degradation
-
(ERAD). Selective degradation of proteins originating in the endoplasmic reticulum (ER) that are recognized as poorly folding and delivered to the ubiquitin proteasome system in the cytosol.
- Ubiquitin proteasome system
-
A cellular system that coordinates the selective degradation of proteins through tagging with ubiquitin, which leads to the target’s degradation by the proteasome.
- Integrated stress response
-
(ISR). A cellular signalling pathway involving the phosphorylation of eukaryotic initiation factor 2α (eIF2α) by one of four stress-sensing kinases: protein kinase RNA-like endoplasmic reticulum kinase (PERK) during endoplasmic reticulum (ER) stress, PKR during some viral infections, HRI during iron deficiency and GCN2 when amino acids are limiting.
- eIF2B
-
The guanine nucleotide exchange factor of eukaryotic initiation factor 2α (eIF2α) that maintains translation initiation, but is inhibited when bound by phosphorylated eIF2α.
- eIF2α
-
A component of the eukaryotic initiation factor 2 (eIF2) complex involved in translation initiation that can be phosphorylated during stress to initiate the integrated stress response (ISR).
- Type I kinase inhibitors
-
Small molecules that bind a kinase’s ATP pocket in its active conformation; inositol-requiring enzyme 1 (IRE1) type I kinase inhibitors promote IRE1’s endonuclease activity.
- Type II kinase inhibitors
-
Small molecules that engage a kinase’s ATP pocket in the inactive configuration; inositol-requiring enzyme 1 (IRE1) type II kinase inhibitors inhibit IRE1’s endonuclease activity, for example the kinase inhibiting RNase attenuator (KIRA) compounds.
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Marciniak, S.J., Chambers, J.E. & Ron, D. Pharmacological targeting of endoplasmic reticulum stress in disease. Nat Rev Drug Discov 21, 115–140 (2022). https://doi.org/10.1038/s41573-021-00320-3
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DOI: https://doi.org/10.1038/s41573-021-00320-3
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