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The unfolded protein response: controlling cell fate decisions under ER stress and beyond

Key Points

  • Alterations in the function of the endoplasmic reticulum (ER) can result in the accumulation of unfolded or misfolded proteins, a cellular condition referred to as ER stress. ER stress engages the unfolded protein response (UPR), an adaptive reaction that reduces unfolded protein load to maintain cell viability and function.

  • Conditions of chronic or irreversible ER stress trigger cell death by apoptosis, a process that involves the activation of the canonical mitochondrial pathway, which is controlled by the B cell lymphoma 2 (BCL-2) protein family. Chronic ER stress has been linked to the occurrence of many diseases, including cancer, neurodegeneration, ischaemia and diabetes.

  • The UPR is a complex signal transduction pathway that is initiated by the activation of at least three UPR stress sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6). These sensors controls adaptive process through both transcriptional and non-transcriptional responses, affecting almost every aspect of the secretory pathway, including protein folding, ER biogenesis, ER-associated degradation (ERAD), protein entry to the ER, autophagy and secretion, among others.

  • UPR signalling has distinct kinetics, intensities and downstream consequences depending on the nature and intensity of the stimuli and the cell type involved. These effects may be explained by the modulation of UPR stress sensor activity through interactions with several modulators and adaptor proteins, which possibly results in the assembly of dynamic signalling platforms that have been referred to as 'UPRosomes'.

  • Recent advances in the UPR field indicate that this pathway has important functions in many physiological processes that are not directly related to protein folding. For example, UPR signalling modules crosstalk with signalling pathways that are key in the control of lipid and energy metabolism, innate immunity and cell differentiation programmes.

Abstract

Protein-folding stress at the endoplasmic reticulum (ER) is a salient feature of specialized secretory cells and is also involved in the pathogenesis of many human diseases. ER stress is buffered by the activation of the unfolded protein response (UPR), a homeostatic signalling network that orchestrates the recovery of ER function, and failure to adapt to ER stress results in apoptosis. Progress in the field has provided insight into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF6). In addition, novel physiological outcomes of the UPR that are not directly related to protein-folding stress, such as innate immunity, metabolism and cell differentiation, have been revealed.

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Figure 1: The UPR.
Figure 2: Cell fate decisions under ER stress.
Figure 3: The stress-sensing mechanism and kinetics of IRE1 signalling.
Figure 4: Multiple checkpoints in the regulation of the UPR.
Figure 5: Novel physiological outcomes of the UPR.

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Acknowledgements

I apologize to all colleagues whose work could not be cited owing to space limitations. I thank A. Couve, U. Woehlbier and A. Glavic for constructive comments, C. Wirth for editing and D. Rodriguez for input into the initial figure design. This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT), Chile, grant 1100176, Fondo de Investigación Avanzado en Areas Prioritarias (FONDAP), Chile, grant 15010006, Millennium Institute grant P09-015-F the Muscular Dystrophy Association, the Michael J. Fox Foundation for Parkinson Research, the Alzheimer's Association and the North American Spine Society.

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Glossary

RIDD

(Regulated IRE1-dependent decay). The degradation of a subset of mRNAs encoding for proteins located in the endoplasmic reticulum, possibly through the activation of the RNase domain of inositol-requiring 1 (IRE1).

ERAD

(Endoplasmic reticulum-associated degradation). A pathway along which misfolded proteins are transported from the ER to the cytosol for proteasomal degradation.

Autophagy

A survival pathway that is classically linked to the adaptation to nutrient starvation through the recycling of cytosolic components by lysosome-mediated degradation. In cells undergoing endoplasmic reticulum stress, autophagy may serve as a mechanism to eliminate damaged organelles and aggregated proteins.

Pancreatic β-cells

Cells in the pancreas that make and secrete insulin to respond to glucose fluctuations.

UPRosome

A signalling platform assembled at the level of inositol-requiring protein 1α that controls the kinetics and amplitude of downstream unfolded protein response (UPR) signalling responses. The UPRosome also orchestrates crosstalk between the UPR and other signalling pathways through the recruitment of different adaptor proteins.

Exocrine pancreas

A type of pancreatic tissue that has ducts arranged in clusters called acini. Cells secrete into the lumen of an acinus a series of enzymes and molecules related to digestion, including trypsinogen, lipase, amylase and ribonuclease.

Endocrine pancreas

The part of the pancreas that acts as an endocrine gland, consisting of the islets of Langerhans, which contain β-cells. Theses cells secrete insulin and other hormones.

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Hetz, C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13, 89–102 (2012). https://doi.org/10.1038/nrm3270

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