Figure 2.

Schematic view of the role of UPR in cell homeostasis and disease. UPR is an adaptive pathway in the ER that promotes homeostasis and increases proteostasis (correct folding and secretion of proteins) in the cell. UPR signaling occurs by activation of three transmembrane sensor proteins in the ER (above right) by mechanisms that are described more in the text. Prolonged or heavily sustained UPR can lead to ER stress that can results in full-blow disease. Some of the mechanisms mediating cell degeneration are shown here including the ASK/JNK and CHOP cell death signaling that in many cases involves activation of caspases. Alterations in calcium handling and oxidative stress occurring in ER stress are not depicted here. UPR and ER stress act in concert with other cell stress pathways involving mitochondria and autophagy. Recent studies have identified small molecular compounds that target the UPR signaling pathways, having beneficial actions in various disease models as discussed in the text. In view of the delicate balance between different pathways in homeostasis it is important to know what would be the best timing for drug treatments to alleviate ER stress (see arrows). In addition, chemical chaperons and other therapies are also potentially useful as drugs in different diseases. Increased knowledge about the role of UPR and ER stress and cellular interactions during cell stress can in the long-run lead to novel treatment strategies in various human disorders.