Endoplasmic Reticulum Stress (ER Stress) and Unfolded Protein Response (UPR) Occur in a Rat Varicocele Testis Model

Figure 1

Schematic representation of the UPR/ER stress pathways. Under stress conditions (such as hyperthermia and hypoxia), unfolded proteins aggregate and accumulate in the lumen of the ER. This triggers the UPR response by driving the BiP/GRP78/HSPA5 protein, an ER chaperone, away from membrane stress sensors of the ER, including inositol-requiring enzyme 1 (IRE1), ATF6, and the PKR-like endoplasmic reticulum kinase (PERK). In short, the sequestration of BiP by unfolded proteins leads to the dimerization of IRE1, its autophosphorylation, revealing an endoribonuclease activity cleaving the mRNA of the ubiquitous X-box 1-binding protein (XBP1u). This generates a cleaved XBP1-binding protein (XBP1s) having a more potent transcriptional activating power on genes coding for more ER chaperones as well as genes involved in the ERAD response (ER-mediated apoptosis). IRE1 also triggers the phosphorylation of the c-Jun-kinase (JNK) which in turn represses the antiapoptotic Bcl2 protein, thus promoting mitochondria-dependent apoptosis signals leading to the activation of caspase-3. Similarly, sequestration of BiP by unfolded proteins in the ER causes the dimerization of PERK, which then exerts its kinase activity on eukaryotic initiation factor 2 (eIF2), resulting in increased translation of ATF4 mRNA resulting in a higher level of the C/EBP homologous protein (CHOP) itself reinforcing ER-mediated apoptosis via transcriptional activation. CHOP, in addition, will stimulate the Bim proapoptotic protein contributing to the reinforcement of mitochondria-dependent apoptosis. BiP sequestration also activates the stress-regulated transcription factor ATF6 [62] that is assumed to directly migrate to the nucleus to activate its target genes. However, recent data suggest that ATF6 acts essentially through CHOP [58]. Finally, the UPR/ER stress generates reactive oxygen species (ROS) that are known to promote apoptosis. Within the ER-stress response, PERK and ROS contribute to stimulate the antioxidant trans-acting factor NRF2 as a way to limit ROS proapoptotic signal.