Innate immune signaling in Drosophila shifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis to support immune function

Autoři: Brittany A. Martínez aff001;  Rosalie G. Hoyle aff002;  Scott Yeudall aff002;  Mitchell E. Granade aff001;  Thurl E. Harris aff001;  J. David Castle aff004;  Norbert Leitinger aff001;  Michelle L. Bland aff001
Působiště autorů: Biomedical Sciences Graduate Program, University of Virginia, Charlottesville, VA, United States of America aff001;  Department of Pharmacology, University of Virginia, Charlottesville, VA, United States of America aff002;  Medical Scientist Training Program, University of Virginia, Charlottesville, VA, United States of America aff003;  Department of Cell Biology, University of Virginia, Charlottesville, VA, United States of America aff004
Vyšlo v časopise: Innate immune signaling in Drosophila shifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis to support immune function. PLoS Genet 16(11): e1009192. doi:10.1371/journal.pgen.1009192
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009192


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 or physiological activation of fat body Toll signaling leads to a tissue-autonomous reduction in triglyceride storage that is paralleled by decreased transcript levels of the DGAT homolog midway, which carries out the final step of triglyceride synthesis. In contrast, Kennedy pathway enzymes that synthesize membrane phospholipids are induced. Mass spectrometry analysis revealed elevated levels of major phosphatidylcholine and phosphatidylethanolamine species in fat bodies with active Toll signaling. The ER stress mediator Xbp1 contributed to the Toll-dependent induction of Kennedy pathway enzymes, which was blunted by deleting AMP genes, thereby reducing secretory demand elicited by Toll activation. Consistent with ER stress induction, ER volume is expanded in fat body cells with active Toll signaling, as determined by transmission electron microscopy. A major functional consequence of reduced Kennedy pathway induction is an impaired immune response to bacterial infection. Our results establish that Toll signaling induces a shift in anabolic lipid metabolism to favor phospholipid synthesis and ER expansion that may serve the immediate demand for AMP synthesis and secretion but with the long-term consequence of insufficient nutrient storage.

Klíčová slova:

Drosophila melanogaster – Enterococcus infections – Fats – Gene expression – Immune response – Larvae – Phospholipids – Phospholipid signaling cascade


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