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Signal integration in the endoplasmic reticulum unfolded protein response

Key Points

  • The endoplasmic reticulum (ER)-localized transmembrane proteins IRE1, PERK and ATF6 detect the load of unfolded protein in the lumen of the organelle, serving as stress receptors. They transduce the ER stress signal to the nucleus to regulate transcription and to the translational apparatus to regulate protein synthesis. Collectively, they signal the unfolded protein response (UPR).

  • Despite the unrelated mechanisms of downstream signalling, significant functional redundancy exists between the three known arms of the UPR. The transcriptional effects of the three arms also overlap significantly, which is achieved, in part, through mutual positive reinforcement.

  • The UPR reprogrammes transcription to enhance the capacity of the ER to cope with misfolded proteins, but also affects the function of the translocon and the repertoire of mRNA translated in the cell. Lipid synthesis is also integrated into the UPR to result in an expansion of the ER, which is especially prominent in professional secretory cells.

  • The UPR enhances the capacity of cells to degrade misfolded ER proteins by two parallel mechanisms: ER associated degradation, in which individual misfolded proteins are retro-translocated to the cytosol for proteasomal degradation, and autophagy — a less selective process in which segments of ER are engulfed by a limiting membrane and trafficked to the lysosome.

  • The three arms of the UPR have powerful pro-survival effects on ER-stressed cells. However, there are examples of failed homeostasis in which specific facets of UPR signalling contribute actively to the death of ER-stressed cells.

  • The pro-survival features of the UPR benefit cancer cells in the hypoxic cores of tumours, raising the possibility that inhibitors of IRE1, PERK or ATF6 might be useful as anti-cancer drugs.

Abstract

The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways — cumulatively called the unfolded protein response (UPR). Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids. The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.

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Figure 1: Signalling by IRE1.
Figure 2: Signalling by ATF6.
Figure 3: Signalling by PERK to the translational machinery.
Figure 4: ER stress and lipid metabolism.
Figure 5: ER stress and cell death.

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Acknowledgements

We are indebted to our laboratory members and trainees who contributed ideas and experiments to many of the studies described here, and we apologize to those colleagues whose publications could not be cited owing to space limitations. Work in our laboratories is supported by the National Institutes of Health (D.R. and P.W.) and the Howard Hughes Medical Institute (P.W.).

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Childhood ataxia with cerebral hypomyelination

Parkinson's disease

Type II diabetes

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Glossary

ER stress

The consequence of a mismatch between the load of unfolded and misfolded proteins in the endoplasmic reticulum and the capacity of the cellular machinery that copes with that load.

Major histocompatibility complex

A plasma-membrane protein complex that binds and displays immunogenic peptides in a characteristic groove structure.

Sterol response element binding protein

A protein from a family of ER-localized membrane-anchored transcription factors that are activated by sterol depletion to bind genes involved in sterol and fatty acid synthesis.

Acute-phase responsive protein

A serum protein secreted by the liver and, to a lesser degree, by other cells in response to systemic inflammation.

Uncharged transfer RNA

A transfer RNA that has not been amino-acylated by its (cognate) amino acid.

Integrated stress response

The consequences of eIF2α phosphorylation on Ser51, which is effected by four different kinases that respond to diverse upstream stress signals, including ER stress.

Amino-acid transporter

A plasma-membrane protein that transports amino acids into cells. Many are transcriptionally activated by ATF4 and, thus, are dependent on the activity of PERK.

Translocon

A proteinaceous channel in the ER membrane, through which nascent proteins are translocated into the ER lumen.

Chaperone reserve

The capacity of an organelle to tolerate a further load of unfolded proteins.

Signal peptide

The portion of a secreted pro-protein that specifies translocation into the ER. It is usually cleaved off following translocation.

Obesity

A metabolic state characterized by excessive accumulation of triglycerides in adipose tissue.

ER-associated protein degradation

The process whereby misfolded ER proteins are delivered to the cytoplasm for proteasomal degradation.

Autophagy

A collection of pathways by which sections of the cytoplasm, including the organelles suspended in it, are sequestered into membrane-bounded compartments that then fuse with lysosomes, where their content is degraded by acid hydrolases.

Ischaemia

The metabolic consequences of inadequate blood supply. It is a common occurrence in large tumours and is associated with a poor response to treatment.

Nude mouse

An immune-compromised mouse that tolerates tumour xenografts and is used to model tumour growth in a living animal.

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Ron, D., Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8, 519–529 (2007). https://doi.org/10.1038/nrm2199

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