Fig. 3.

The temporal dynamics of the UPR.

The UPR stimuli typically activate all three branches. Both IRE1 and ATF6 are stimulated in an acute, transient manner, which is largely cytoprotective. The diminishment of IRE1 and ATF6 when facing long-lasting stress, combined with persistent activation of PERK, leads to augmentation of the pro-apoptotic signaling and cell death. Note that the pro-apoptotic property of the IRE1 signaling may be induced by irremediable protein folding stress, which contributes to cellular demise under conditions of pathological chronic activation of the UPR. The temporal dynamics of the UPR therefore plays a pivotal role in determining cell fate in response to various stresses.