ER stress

ER stress unfolded protein response. All cells regulate the capacity of their ER to fold and process client proteins and they adapt to an imbalance between client protein load and folding capacity (ER stress).

The unfolded protein response is mediated by several proteins that reside in and span the ER membrane. The luminal domains of these proteins sense perturbations in protein folding, and the cytoplasmic domains activate signaling pathways that reduce the levels of misfolded proteins in the cell, by increasing the production of chaperones and slowing down protein translation.

Paradoxically, the activation of the unfolded protein response also nduced by unfolded and misfolded proteins. Unfolded or misfolded proteins accumulate in the ER and trigger a number of cellular responses, collectively called the leads to cell death by activating caspases, particularly an ER-resident caspase called caspase-12 (CASP12).

Thus, misfolded proteins initially trigger the cytoprotective function of this response, but if these abnormal proteins persist, the pro-apoptotic cytotoxic functions take over. Aggregation of abnormally folded proteins, caused by genetic mutations, aging, or unknown environmental factors, is now recognized as a feature of a number of neurodegenerative diseases, including Alzheimer disease, Huntington disease, and Parkinson disease, and possibly type II diabetes.

Deprivation of glucose and oxygen, and stress such as heat, also result in protein misfolding and trigger the unfolded protein response, culminating in cell injury and death.

Pathology

 RNA translation diseases

• Wolcott-Rallison syndrome

Mutations affecting EIF2AK3 gene (MIM.604032), the ER stress-activated pancreatic ER kinase (or PERK), and its downstream effector, the translation initiation complex eukaryotic initiation factor 2 (eIF2), have a profound impact on islet cell development, function, and survival.

EIF2AK3 mutations are associated with the Wolcott-Rallison syndrome of infantile diabetes and mutations that prevent the alpha-subunit of eIF2 from being phosphorylated by EIF2AK3, block beta-cell development, and impair gluconeogenesis.

 diabetes

The early steps of insulin biosynthesis occur in the endoplasmic reticulum (ER), and the beta-cell has a highly developed and active ER.

See also

 Endoplasmic Reticulum

• smooth endoplasmic reticulum (SER)
• rough endoplasmic reticulum (RER)

References

 Rao RV, Bredesen DE. Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr Opin Cell Biol. 2004 Dec;16(6):653-62. PMID: 15530777

 Shi Y, Taylor SI, Tan SL, Sonenberg N. When translation meets metabolism: multiple links to diabetes. Endocr Rev. 2003 Feb;24(1):91-101. PMID: 12588811

 Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes. 2002 Dec;51 Suppl 3:S455-61. PMID: 12475790