Programmed cell death during chronic/high ER stress is an active process, and is promoted by alternate outputs of the UPR itself, which bias cell fate away from adaptation to the opposite extreme of cell destruction (Han et al., 2009). As activation levels of IRE1α, PERK, and ATF6 reflect either an adapted ER, or the continued presence of unfolded proteins, these upstream sensors are centrally poised to participate in the switching process between adaptation and destruction. However, many other key downstream links in this switching process remain to be discovered, and their elucidation may provide inroads to treat diseases of cell loss.
