Alternatively, cells may experience ER stress at levels that are high—or prolonged—enough to overwhelm adaptive responses. Such irremediable ER stress can result from genetic mutations causing improper folding or modification of encoded secretory proteins. A well-studied example is the unoxidizable mutant form of murine proinsulin—called Akita—that cannot form an intramolecular disulfide bond needed to fold in the ER. Buildup of Akita in β-cells triggers programmed cell death, leading to a dominantly inherited form of diabetes in the mutant mice (Oyadomari et al., 2002; Wang et al., 1999); similar diabetes-causing mutations in the proinsulin gene occur in humans (Stoy et al., 2007). Irremediable ER stress can also be caused by pharmacologically inhibiting important ER protein modification processes. Under chronic and uncorrected ER stress, a terminal UPR becomes activated to trigger programmed cell death (Merksamer and Papa, 2010; Shore et al., 2011). Multi-cellular organisms may have evolved the ability to cull irremediably-stressed cells through programmed cell death in order to prevent production of improperly-modified or misfolded proteins. However, massive cell loss, which goes unmatched by cell proliferation, can lead to cell degenerative diseases.
