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. 2024 Jun 7;81(1):250. doi: 10.1007/s00018-024-05286-0

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — The UPR^ER. A Adaptive UPR^ER. Following ER stress, BiP binds to misfolded proteins on the substrate-binding site and the ATPase domain dissociates from the transmembrane receptors, allowing allosteric activation of the UPR^ER regulators by oligomerisation and phosphorylation [14, 15]. (1) IRE1α RNase activity mediates unconventional splicing of XBP1 [16–18], XBP1s translocates to the nucleus to promote expression of genes related to quality control [9, 19]. IRE1α also mediates the cleavage and degradation of mRNAs and microRNAs; regulated IRE1α-dependent decay (RIDD), decreasing the protein load in the ER lumen [20]. (2) PERK phosphorylates eIF2α [21], promoting rapid attenuation of global mRNA translation [22, 23]. Phosphorylated eIF2α also regulates the translation of the transcription factor ATF4 [24]. ATF4 regulates the feedback loop responsible for the restoration of protein synthesis. ATF4 induction of CHOP, upregulates the expression of GADD34 which forms a complex with PP1 to dephosphorylate eIF2α [25, 26]. (3) ATF6α translocates to the Golgi apparatus, where it is cleaved to generate ATF6f, which acts as a transcription factor that promotes the expression of ER chaperones [27, 28]. ATF6α promotes the expression of Xbp1 mRNA, enhancing the substrate load for IRE1α splicing [29]. B Maladaptive UPR^ER. Following prolonged ER stress the homeostatic capacity of the UPR^ER becomes saturated that can activate pro-apoptotic signalling. (1) IRE1α interacts with TRAF2 to promote a kinase signalling cascade that activates JNK [30, 31]. JNK promotes the oligomerisation of BAX and BAK on the mitochondrial membrane and the assembly of the apoptosome [32, 33]. RIDD can promote apoptosis by degrading essential cell-survival mRNAs such as the negative regulators of TXNIP, promoting the assembly of the inflammasome leading to apoptosis [34, 35]. (2) PERK-eIF2α induces the translation of ATF4, activation of CHOP and GADD34 [25, 26]. CHOP promotes the expression of PUMA, NOXA, BIM and BID, which induce the mitochondrial BCL-2 pro-apoptotic proteins. CHOP can also activate the translation of ERO1α, promoting the oxidation of the ER environment [36, 37]. PERK-ATF4-CHOP arm regulates IP3R-mediated Ca²⁺ leakage from the ER [38, 39]. Sustained and excessive Ca²⁺ transport from the ER to the mitochondria impairs mitochondrial metabolism and lead to opening of the mPTP and pro-apoptotic signalling [40, 41]