Endoplasmic Reticulum Stress

The endoplasmic reticulum (ER) is the cellular organelle that is critical for protein folding and secretion, calcium homeostasis, and lipid biosynthesis. The ER is the site of multiple post-translational modifications such as glycosylation and disulfide bond formation. It is also the organelle in which proteins are folded into their proper conformation and in which multi-subunit proteins are assembled. Under various conditions, called ER stress, protein folding in the ER is impaired leading to the accumulation of misfolded proteins. Multiple cellular disturbances can cause ER stress including disturbances in redox regulation, calcium regulation, glucose deprivation, and viral infection.

The accumulation of misfolded proteins in the ER is harmful to cells and thus the ER has evolved mechanisms designed to detect misfolded proteins and either refold them or target them for degradation. The accumulation of misfolded proteins in the ER triggers an evolutionarily conserved program called the unfolded protein response (UPR) which is designed to clear the ER of misfolded proteins and restore ER homeostasis. This response includes the attenuation of protein translation to lessen the protein processing load in the ER. There is also an upregulation of genes involved in ER protein folding including chaperones such as BiP/GRP78, enzymes mediating folding such as protein disulfide isomerase, ER structural components, and components of the ER-associated degradation pathway (ERAD). Proteins that can not be refolded into their correct conformation are targeted to the ER-associated degradation (ERAD) pathway where they are ubiquinated and degraded via the proteasomal system.

The ER stress response is initiated when the capacity of ER-resident chaperone proteins is exceeded by the load of misfolded proteins. Protein chaperones like BiP/GRP78, Grp 94, and calreticulin assist in proper protein folding. BiP/GRP78, a transmembrane protein that spans the ER lumen, associates with the UPR sensors ATF6, IRE1, and PERK and represses their activity. The accumulation of misfolded proteins results in the saturation of ER chaperones, including BiP/GRP78. The sequestering of BiP by misfolded proteins results in the loss of BiP-mediated repression of the UPR sensors resulting in their activation. Prolonged ER stress typically results in cell death by apoptosis.

ER stress occurs in both normal and pathophysiological conditions. The efficient development of plasma cells from B cells requires components of the UPR. However, ER stress has also been implicated in multiple disorders such as type 2 diabetes, ischemia, and neurodegenerative disorders. ER stress can also be induced by hypoxia. This has implications for solid tumors which usually exhibit hypoxia in their cores. SCID mice implanted with tumor-forming cells that lack UPR components generate smaller tumors than those implanted with wild-type controls suggesting that the UPR contributes to cancer cell survival. Insulin resistance is also associated with ER stress and the treatment of type 2 diabetic mice with chemical chaperones which assist protein folding in the ER restored insulin sensitivity.

(1) Hotamisligil, G.S., Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease. Cell 140, 900-917 (2010).
(2) Lin, J.H. et al., Endoplasmic Reticulum Stress in Disease Pathogenesis. Annu. Rev. Pathol. Mech. Dis. 3, 399-425 (2008).
(3) Tse, Y.C., and Weissman, A.M., The Unfolded Protein Response, Degradation from Endoplasmic Reticulum and Cancer. Genes Cancer 1, 764-778 (2010).
(4) Xu, C. et al., Endoplasmic Reticulum Stress: Cell Life and Death Decisions. J. Clin. Invest. 115, 2656-2664 (2005).

Chemical Activators and Inhibitors of ER Stress

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B7651 Brefeldin A from Penicillium brefeldianum, ≥99% (HPLC and TLC)
B5936 Brefeldin A from Penicillium brefeldianum, Ready Made Solution, 10 mg/mL in DMSO, 0.2 μm filtered
C7522 Calcium Ionophore A23187 ≥98% (TLC), powder
C3394 Cordycepin from Cordyceps militaris
SML0031 DBeQ ≥98% (HPLC)
D9160 1-Deoxymannojirimycin hydrochloride
D0632 DL-Dithiothreitol ≥98% (HPLC), ≥99.0% (titration)
K1140 Kifunensine mannosidase inhibitor
P21005 4-Phenylbutyric acid 99%
SML1085 Retro-2 ≥98% (HPLC)
T0266 Sodium tauroursodeoxycholate ≥95%
T9033 Thapsigargin ≥98% (HPLC), solid film
T7765 Tunicamycin from Streptomyces sp.

Chemical ER Chaperones

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D2650 Dimethyl sulfoxide Hybri-Max, sterile-filtered, BioReagent, suitable for hybridoma, ≥99.7%
P21005 4-Phenylbutyric acid 99%
T0266 Sodium tauroursodeoxycholate ≥95%
T0514 Trimethylamine N-oxide dihydrate 98%
U5127 Ursodeoxycholic acid ≥99%

ER Resident Proteins

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B1174 BiP from calf liver ~96% (SDS-PAGE)
C4714 Calreticulin from bovine liver ≥90% (SDS-PAGE), lyophilized powder
H9776 Heat Shock Protein 70 from bovine brain >95% (SDS-PAGE), lyophilized powder
H7283 Heat Shock Protein 70 human recombinant, expressed in E. coli, buffered aqueous solution, ≥90% (SDS-PAGE)
SRP4858 Heat Shock Protein 90 human recombinant, expressed in baculovirus infected Sf9 cells, ≥99% (SDS-PAGE)
P3818 Protein Disulfide Isomerase from bovine liver >95% (SDS-PAGE), ≥100 units/mg protein, lyophilized powder

Proteasome Inhibitors

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A6185 Calpain Inhibitor I ≥97% (TLC), powder
A6060 Calpain Inhibitor II powder
G9893 Gliotoxin from Gliocladium fimbriatum
L6785 Lactacystin ≥90% (HPLC)
D5946 PD 150606 ≥97% (HPLC)
C6706 Z-Leu-Leu-Norvalinal ≥90% (HPLC), powder