Figure 1.

Adaptive and maladaptive mechanisms of UPR signaling. Following the onset of ERS in the cardiac system, cardiac-specific UPR is activated, and the three branches of signaling transducers (PERK, IRE1, and ATF6) are activated. Furthermore, downstream of the three UPR signaling pathways, transcription factors are also activated, and unfolded protein response (UPR) associated genes are upregulated. In general, activation of the UPR signaling networks initiates attenuation of the global protein translation, synthesis of folding chaperones and enzymes, and ERAD of misfolded/unfolded proteins in the ER lumen. Thus, through coordinated attenuation of global protein synthesis, upregulation of ER-resident chaperones, and activation of ERAD, the UPR often manages to resolve/restore acute homeostasis imbalances caused by various stimuli; thus, the cells survive (adaptive mechanism). The primary goal of the UPR activation is to avoid damages caused by the ERS through its adaptive functional role, which reestablishes the ER homeostasis, enhancing cell survival. However, intense ERS makes the cells succumb to apoptosis death (maladaptive mechanism). Once the ERS turns out to be persistent, transcription factors including CHOP, JNK, and caspases are activated, and members of the Bcl family such as Bcl-2 are suppressed, thereby eliciting programmed cell death.