**3. ER stress and the unfolded protein response (UPR)**

The ER is the main region in the cell where protein synthesis and post-synthesis changes take place, where newly synthesized proteins are folded and combined. The ER is extremely sensitive to many factors that will affect this function [37]. In case of any problem, misfolded or unfolded proteins begin to accumulate in the cytoplasm. When the protein concentration accumulated in the cytoplasm increases, the ER cannot cope with this load, and this causes the functioning to be worse [38]. Eukaryotic cells can adapt by reducing the rate of protein synthesis, upregulating the expression of genes encoding chaperones and other proteins that prevent polypeptide aggregation, and disrupting accumulated misfolded proteins. This set of cellular responses is obtained after activation of an integrated intracellular signaling cascade: the "Unfolded Protein Response" (UPR) [39]. The UPR is regulated by three sensor proteins known as PERK (PKR-like ER kinase), IRE1\_ (inositol-requiring transmembrane kinase/endoribonuclease 1), and ATF6 (activating transcription factor 6). These proteins are associated with BiP or GRP78 (78 KDa glucose-regulated protein) and therefore remain inactive [29]. BiP is released under ER stress, and the response is shaped by further dimerization and autophosphorylation of PERK and IRE1 [40, 41]. The UPR cascade is activated after regulated intramembrane proteolysis of another regulatory sensor protein, ATF6, against the UPR [42] (**Figure 2**).

**Figure 2.** *The UPR. UPR is controlled by three sensor proteins [43].*
