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 restore cellular homeostasis through multiple intracellular signalling pathways. In mammals, the UPR programme regulates the expression of hundreds of genes in response to signalling from ATF6, IRE1, and PERK. These three highly 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 an increase of specific sphingolipids. As a result, the UPR supports cellular robustness as a broad-spectrum compensatory pathway that is achieved by deploying a tailored transcriptional programme adapted to the source of ER stress. This review summarises the current understanding of the three ER stress transducers in sensing proteotoxic stress and LBS. The plasticity of the UPR programme in the context of different sources of ER stress will also be discussed.