ABSTRACT
Cold affects many aspects of biology, medicine, agriculture, and industry. Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies.
Subject(s)
Cold-Shock Response , Lipid Metabolism , Animals , Humans , Cold Temperature , Endoplasmic Reticulum Stress , LipidsABSTRACT
Metabolic diseases often share common traits, including accumulation of unfolded proteins in the endoplasmic reticulum (ER). Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage which weakens with age. Here, we show that Caenorhabditis elegans fed a bacterial diet supplemented high glucose at day 5 of adulthood (HGD-5) extends their lifespan, whereas exposed at day 1 (HGD-1) experience shortened longevity. We observed a metabolic shift only in HGD-1, while glucose and infertility synergistically prolonged the lifespan of HGD-5, independently of DAF-16. Notably, we identified that UPR stress sensors ATF-6 and PEK-1 contributed to the longevity of HGD-5 worms, while ire-1 ablation drastically increased HGD-1 lifespan. Together, we postulate that HGD activates the otherwise quiescent UPR in aged worms to overcome ageing-related stress and restore ER homeostasis. In contrast, young animals subjected to HGD provokes unresolved ER stress, conversely leading to a detrimental stress response.
Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Animals , Caenorhabditis elegans/metabolism , Longevity , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Glucose/metabolism , Unfolded Protein Response , Endoplasmic Reticulum Stress/physiologyABSTRACT
Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated, and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.
Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans/genetics , Endoplasmic Reticulum Stress/genetics , Heat-Shock Proteins/genetics , Lipid Bilayers/chemistry , Membrane Glycoproteins/genetics , Protein Serine-Threonine Kinases/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae/genetics , Unfolded Protein Response , Animals , Biosensing Techniques , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/metabolism , Chromatin/chemistry , Chromatin/metabolism , Endoplasmic Reticulum , Gene Expression Profiling , Gene Expression Regulation , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Heat-Shock Proteins/metabolism , Homeostasis/genetics , Intracellular Membranes/metabolism , Intracellular Membranes/ultrastructure , Lipid Bilayers/metabolism , Lipid Metabolism/genetics , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Membrane Glycoproteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Transcription, Genetic , Red Fluorescent ProteinABSTRACT
Metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD), are emerging as epidemics that affect the global population. One facet of these disorders is attributed to the disturbance of membrane lipid composition. Perturbation of endoplasmic reticulum (ER) homeostasis through alteration in membrane phospholipids activates the unfolded protein response (UPR) and causes dramatic transcriptional and translational changes in the cell. To restore cellular homeostasis, the three highly conserved UPR transducers ATF6, IRE1 (also known as ERN1 in mammals) and PERK (also known as EIF2AK3 in mammals) mediate adaptive responses upon ER stress. The homeostatic UPR cascade is well characterised under conditions of proteotoxic stress, but much less so under lipid bilayer stress-induced UPR. Here, we show that disrupted phosphatidylcholine (PC) synthesis in Caenorhabditiselegans causes lipid bilayer stress, lipid droplet accumulation and ER stress induction. Transcriptional profiling of PC-deficient worms revealed a unique subset of genes regulated in a UPR-dependent manner that is independent from proteotoxic stress. Among these, we show that autophagy is modulated through the conserved IRE-1-XBP-1 axis, strongly suggesting of the importance of autophagy in maintaining cellular homeostasis during the lipid bilayer stress-induced UPR.
