The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation

  title={The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation},
  author={Peter Walter and David Ron},
  pages={1081 - 1086}
The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein-folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the… 

Ascorbic acid 6-palmitate modulates microglia M1/M2 polarization in lipopolysaccharide-stimulated BV-2 cells via PERK/elF2α mediated endoplasmic reticulum stress

It is revealed that ascorbic acid 6-palmitate possessed its effect on the reconstruction of microglia M1/M2 polarization balance in LPS-stimulated BV-2 cells via modulating PERK/elF2α mediated ER stress.

Forest Biomass as a Promising Source of Bioactive Essential Oil and Phenolic Compounds for Alzheimer’s Disease Therapy

EO and phenolic extracts, and especially their major compounds, were found to prevent several pathological cellular processes and to improve cognitive function in AD animal models, suggesting Eucalyptus globulus leaves are a relevant source of biological active and safe molecules that could be used as raw material for nutraceuticals and plant-based medicinal products useful for AD prevention and treatment.

Norketamine, the Main Metabolite of Ketamine, Induces Mitochondria-Dependent and ER Stress-Triggered Apoptotic Death in Urothelial Cells via a Ca2+-Regulated ERK1/2-Activating Pathway

NK exposure exerts urothelial cytotoxicity via a [Ca2+]i-regulated ERK1/2 activation, which is involved in downstream mediation of the mitochondria-dependent and ER stress-triggered apoptotic pathway, consequently resulting in uroselial cell death.

Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

Growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics.

Celecoxib-Dependent Neuroprotection in a Rat Model of Transient Middle Cerebral Artery Occlusion (tMCAO) Involves Modifications in Unfolded Protein Response (UPR) and Proteasome

The ability of celecoxib treatment on reducing the ER stress correlates with the enhancement of IRE1-UPR pathway and UPS degradation, which supports the ability of anti-inflammatory therapy in modulating ER stress and reveals the IRE 1 pathway as a promising therapeutic target in stroke therapy.

Probing the unfolded protein response in long-lived naked mole-rats

ER Stress Responses: An Emerging Modulator for Innate Immunity

The causes and consequences of ER stress activation in the myeloid compartment are discussed with a special focus on the crosstalk between ER, innate signaling and metabolic environments.

The microRNAs miR-211-5p and miR-204-5p modulate ER stress in human beta cells.

Observations identify a novel crosstalk between miRNAs, ER stress and beta cell apoptosis in early type 1 diabetes.

Estrogen-Induced Apoptosis in Breast Cancers Is Phenocopied by Blocking Dephosphorylation of Eukaryotic Initiation Factor 2 Alpha (eIF2α) Protein

The results not only elucidate the mechanism of estrogen-induced apoptosis but also identify a drugable target for potential therapeutic intervention that can mimic the beneficial effect of estrogen in some breast cancers.



Endoplasmic reticulum stress and pancreatic β-cell death

CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum.

This work finds that CHOP directly activates GADD34, which promotes ER client protein biosynthesis by dephosphorylating phospho-Ser 51 of the alpha-subunit of translation initiation factor 2 (eIF2alpha) in stressed cells, and protects cells from ER stress by decreasing client protein load and changing redox conditions within the organelle.

Unfolded Proteins Are Ire1-Activating Ligands That Directly Induce the Unfolded Protein Response

It is found that the core ER-lumenal domain (cLD) of yeast Ire1 binds to unfolded proteins in yeast cells and to peptides primarily composed of basic and hydrophobic residues in vitro.

Signalling pathways in the unfolded protein response: development from yeast to mammals.

  • K. Mori
  • Biology
    Journal of biochemistry
  • 2009
The mechanisms and activation consequences of UPR signalling pathways in yeast, worm, fly and mammalian cells are summarized and how they have evolved to counteract ER stress effectively is discussed.

Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response

The studies identify human Ire1α as a target for development of ATP‐competitive inhibitors that will modulate the UPR in human cells, which has particular relevance for myeloma and other secretory malignancies.

Selective Inhibition of a Regulatory Subunit of Protein Phosphatase 1 Restores Proteostasis

Without affecting the related PPP1R15B-phosphatase complex and constitutive protein synthesis, guanabenz prolonged eIF2α phosphorylation in human stressed cells, adjusting the protein production rates to levels manageable by available chaperones, and rescued cells from protein misfolding stress.

Sensing ER Stress

On page 1891 in this issue, Gardner and Walter (1) describe a molecular mechanism by which the sensor protein Ire1 detects and communicates ER stress.