During periods of irremediable ER stress, as observed in pathological conditions such as neurodegeneration and type II diabetes, IRE1α becomes hyper-activated leading to apoptosis driven by promiscuous IRE1α RNase activity and/or activation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream target c-jun NH2-terminal kinase (JNK) [33], [37], [38], [39]. Here, MAP3K5 is linked to type 2 diabetes mellitus.