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.

Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants.

Sphingolipid metabolites are involved in the regulation of autophagy, a degradative recycling process that is required to prevent neuronal degeneration. Drosophila blue cheese mutants neurodegenerate due to perturbations in autophagic flux, and consequent accumulation of ubiquitinated aggregates. Here, we demonstrate that blue cheese mutant brains exhibit an elevation in total ceramide levels; surprisingly, however, degeneration is ameliorated when the pool of available ceramides is further increased, and exacerbated when ceramide levels are decreased by altering sphingolipid catabolism or blocking de novo synthesis. Exogenous ceramide is seen to accumulate in autophagosomes, which are fewer in number and show less efficient clearance in blue cheese mutant neurons. Sphingolipid metabolism is also shifted away from salvage toward de novo pathways, while pro-growth Akt and MAP pathways are down-regulated, and ER stress is increased. All these defects are reversed under genetic rescue conditions that increase ceramide generation from salvage pathways. This constellation of effects suggests a possible mechanism whereby the observed deficit in a potentially ceramide-releasing autophagic pathway impedes survival signaling and exacerbates neuronal death.