Lipid bilayer stress and proteotoxic stress-induced unfolded protein response deploy divergent transcriptional and non-transcriptional programmes

The unfolded protein response (UPR) is activated by endoplasmic reticulum (ER) stress and is designed to restorecellular homeostasis through multiple intracellular signalling pathways. In mammals, the UPR programmeregulates the expression of hundreds of genes in response to signalling from ATF6, IRE1, and PERK. These threehighly conserved stress sensors are activated by the accumulation of unfolded proteins within the ER.Alternatively, IRE1 and PERK sense generalised lipid bilayer stress (LBS) at the ER while ATF6 is activated by anincrease of specific sphingolipids. As a result, the UPR supports cellular robustness as a broad-spectrum com-pensatory pathway that is achieved by deploying a tailored transcriptional programme adapted to the source ofER stress. This review summarises the current understanding of the three ER stress transducers in sensingproteotoxic stress and LBS. The plasticity of the UPR programme in the context of different sources of ER stresswill also be discussed.Accepted versio