Fig. 1

Endoplasmic reticulum (ER) stress is the result of an imbalance or disturbance in the normal functioning of the ER, a cellular organelle involved in protein production and folding. An excess of misfolded proteins, a calcium imbalance, a viral infection, or dietary deficiency can all contribute to this. When ER stress occurs, a cellular signaling cascade called the unfolded protein response (UPR) is triggered. It aims to reduce stress and return to ER equilibrium. IRE1, PERK, and ATF6 are the three primary branches of the UPR that are mediated by distinct ER transmembrane proteins. IRE1 pathway: IRE1 splices and processes XBP1 mRNA to produce a transcription factor that activates genes related to ER-associated degradation and protein folding. PERK pathway: eIF2α is phosphorylated by PERK, which causes an overall decrease in protein synthesis. It preferentially stimulates the translation of ATF4, which controls the expression of genes related to the metabolism of amino acids, apoptosis, and antioxidant responses. ATF6 pathway: after being delivered to the Golgi apparatus, ATF6 cleaves and releases a fragment of a transcription factor. After translocating to the nucleus, this fragment activates genes related to lipid metabolism, ER-associated degradation, and protein folding. Stress reduction and ER function restoration are the primary objectives of the UPR. Normality is restored to cellular activities upon resolution of the stress. On the other hand, apoptotic mechanisms may cause cell death in response to extended or severe ER stress. Created by https://www.biorender.com/