Innate immune signaling in Drosophila shifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

During infection, cellular resources are allocated toward the metabolically-demanding processes of synthesizing and secreting effector proteins that neutralize and kill invading pathogens. In Drosophila, these effectors are antimicrobial peptides (AMPs) that are produced in the fat body, an organ that also serves as a major lipid storage depot. Here we asked how activation of Toll signaling in the larval fat body perturbs lipid homeostasis to understand how cells meet the metabolic demands of the immune response. We find that genetic activation of fat body Toll signaling leads to a tissue-autonomous reduction in triglyceride storage that is paralleled by decreased transcript levels of Lipin, which synthesizes diacylglycerol, and midway, which carries out the final step of triglyceride synthesis. In contrast, we discovered that Kennedy pathway enzymes, such as easily shocked and Pcyt1, that synthesize membrane phospholipids are induced by the Toll pathway. Mass spectrometry analysis revealed elevated levels of major phosphatidylcholine and phosphatidylethanolamine species in fat bodies with active Toll signaling. The induction of Kennedy pathway enzymes in response to Toll signaling required the unfolded response mediator Xbp1 but was blunted by deleting AMP genes and thereby reducing secretory demand elicited by Toll activation. Consistent with these findings, endoplasmic reticulum volume is expanded in fat body cells with active Toll signaling, as determined by transmission electron microscopy. Our results establish that Toll signaling induces a shift in anabolic lipid metabolism, accompanied by changes in key lipid synthesis enzymes, that may serve the immediate demand for AMP synthesis and secretion but that ultimately leads to the long-term consequence of insufficient nutrient storage.Author summaryFighting infection requires that immune cells synthesize antimicrobial peptides and antibodies and carry out cellular processes like phagocytosis to destroy microbes and clear infected cells. During infection, metabolic processes support and direct immune function. Here, we use the fruit fly Drosophila melanogaster as a model system to understand the interaction between immunity and metabolism. In Drosophila larvae, infection leads to tremendous production of antimicrobial peptides that destroy invading microbes. These peptides are made in the fat body, an organ that is also the site of fat storage. Activating the immune response reduces lipid storage but increases the production of phospholipids that form the membranes of organelles such as the endoplasmic reticulum. This organelle is the starting point for synthesis and secretion of antimicrobial peptides, and its volume is increased in response to immune activation. Shifting metabolism from fat storage to membrane phospholipid synthesis supports the immune response. However, this comes at the expense of the ability to withstand other types of stress such as food scarcity. These findings are important because they suggest that some of the metabolic changes induced by fighting infection may become pathological if they are maintained over long periods of time.