Targeting the Endoplasmic Reticulum Unfolded Protein Response to Counteract the Oxidative Stress-Induced Endothelial Dysfunction

Figure 1

The signalling pathways of UPR. (a) During normal conditions, Bip/GRP78 binding to IRE1α, PERK, and ATF6α maintains the three transducers in an inactive state. In stressed conditions, Bip/GRP78 dissociates from IRE1α, PERK, and ATF6α to help the folding of secretory proteins and allows the activation of the transducers [28]. (b) After the release from Bip/GRP78, IRE1α dimerizes and autophosphorylates to activate its kinase and endoribonuclease domains [15]. Activated IRE1α cleaves 26 nucleotides from the mRNA encoding the X-box-binding protein 1 (XBP1) allowing the translation of XBP1 [140]. Bip/GRP78 dissociation enables also PERK activation through dimerization and trans-autophosphorylation. Activated PERK phosphorylates eIF2α at Ser51 leading to attenuation of protein synthesis, thereby reducing ER protein load. During this condition, some mRNA, such as the activating transcription factor 4 (ATF4) mRNA, are preferentially translated [141]. During severe ER stress, ATF4 strongly induces CHOP that triggers the apoptotic programme in different ways [31]. The eIF2α-ATF4 axis can also be activated by other cytosolic kinases allowing the regulation of global protein synthesis and the preferential translation of specific mRNA in response to different stimuli in a convergent signalling pathway known as integrated stress response (ISR) [20, 30]. ATF6α is the third ER stress sensor located in the ER membrane. Upon ER stress and release by Bip/GRP78, ATF6α is packaged into COPII vesicles and transferred to the cis-Golgi where it undergoes intramembrane proteolysis-specific cleavage by site 1 protease (S1P) and S2P to produce a transcriptionally active fragment (pATF6α). (c) XBP1, ATF4, and pATF6α migrate into the nucleus to activate the transcription of specific UPR genes involved in protein folding and trafficking, ERAD, cellular metabolism, autophagy, and apoptosis [20, 142]. Bip: Bip/GRP78; uXBP1: unspliced XBP1; sXBP1: spliced XBP1.

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