The endoplasmic reticulum is responsible for much of a cell’s protein synthesis and folding, but it also has an important role in sensing cellular stress. The endoplasmic reticulum (ER) is the site of synthesis, folding and modification of secretory and cell-surface proteins, as well as the resident proteins of the secretory pathway. The quality control machinery in the ER operates in conjunction with protein folding pathways and is so selective that even relatively minor perturbations in the efficiency of protein folding can cause the rejection of nascent proteins as misfolded and, consequently, the accumulation or degradation of these proteins. Thus, the ER also contains resident molecules with a primary function of sensing protein misfolding in this organelle and initiating changes in gene expression, which impact the folding capacity of the ER.
The accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) induces a coordinated adaptive program called the unfolded protein response (UPR). The UPR alleviates stress by upregulating protein folding and degradation pathways in the ER and inhibiting protein synthesis. Physiological conditions that induce the UPR by causing protein misfolding include: the differentiation and development of professional secretory cells, such as plasma or pancreatic b cells; altered metabolic conditions, such as glucose deprivation, hyperhomocysteinemia and ischemia; mutations in the genes encoding secretory or transmembrane proteins, which normally fold in the ER, such as a-1 antitrypsin and insulin; and infection by certain pathogens, such as hepatitis C. To date, three ER-resident transmembrane proteins have been identified as proximal sensors of the presence of ER stress: the kinase and endoribonuclease IRE1 (a and b), the PERK kinase and the basic leucine-zipper transcription factor ATF6 (a and b). In the cases of IRE1 and PERK, which both have cytoplasmic serine/threonine kinase domains, ER stress induces lumenal-domaindriven homodimerization, autophosphorylation and activation. The activation of all three components of the UPR depends on the dissociation of the proximal signaling molecule from the abundant lumenal chaperone BiP. The combined effects of the activation of these molecules are an upregulation of genes encoding proteins that are involved in the secretory pathway, such as ER-resident chaperones and proteins involved in ER-associated protein degradation, and a downregulation of protein synthesis, reducing the influx of nascent proteins into the ER. Sustained unresolved ER stress leads to apoptosis.
Aging linked declines in expression and activity of key ER molecular chaperones and folding enzymes compromise proper protein folding and the adaptive response of the UPR. One mechanism to explain age-associated declines in cellular functions and age-related diseases is a progressive failure of chaperoning systems. In many of these diseases, proteins or fragments of proteins convert from their normally soluble forms to insoluble fibrils or plaques that accumulate in a variety of organs including the liver, brain or spleen. This group of diseases, which typically occur late in life includes Alzheimer's, Parkinson's, type II diabetes and a host of less well known but often equally serious conditions such as fatal familial insomnia. The UPR is implicated in many of these neurodegenerative and familial protein folding diseases as well as several cancers and a host of inflammatory diseases including diabetes, atherosclerosis, inflammatory bowel disease and arthritis.