Unfolded protein response - ER
Correctly folding proteins is a severely complicated process that fails at times, despite the controlled environment of the ER and numerous molecular helpers. Under normal conditions, these misfolded proteins are degraded through the ER-associated degradation (ERAD) mechanism. However, various physiological or environmental stressors can inhibit or overwhelm these normal mechanisms resulting in an increase in the amount of misfolded proteins, which trigger the Unfolded Protein Response (UPR). Organisms have evolved the UPR to handle this ER stress and suppress the toxicity of accumulated misfolded proteins (proteotoxicity). In mammals the UPR attenuates protein synthesis through PERK/PEK1 and increases transcription of folding and ERAD components through activation of potent transcription factors through IRE1 splicing of XBP1 mRNA and ER-stress cleavage of ATF-6. These events ultimately augment folding and enhance degradation capacity of the organelle. In C. elegans, the UPR also activates transcriptional regulators that reduce protein synthesis and increase the number of components necessary to deal with misfolded proteins.
ER-associated degradation
Correctly folding proteins is a severely complicated process. Within eukaryotes an optimal environment for protein folding is provided by the endoplasmic reticulum (ER). In addition, proper folding requires the activity of numerous molecular chaperones and folding enzymes. Despite the controlled environment and numerous molecular helpers, misfolded proteins do sometimes occur. ER-associated degradation (ERAD) is a normal cell function that detects and deals with these occurrences. Through the ERAD process, misfolded proteins are recognized, retrotranslocated to the cytosol, ubiquinated, and then degraded by the proteosome.
Proteostasis
Proper protein function relies on a balanced system of protein synthesis, folding, trafficking and degradation to ensure a homeostatic concentration of properly processed proteins in the organism. Disruptions in any one of these events can result in alterations in the level of proteins, the accumulation of misfolded proteins, and or the aggregation of proteins. Stress responses in the cytoplasm, mitochondria, and ER keep properly folded protein concentrations in check. These systems maintain proteostasis by up-regulating or down-regulating transcriptional and translational processing of proteins or by increasing protein degradation pathways. Many disease states in humans, such as cystic fibrosis, and Alzheimer's, Parkinson's and Huntington's diseases have been attributed to the breakdown of proteostasis systems in the cell.