PLOS Genetics ( IF 4.5 ) Pub Date : 2020-11-23 , DOI: 10.1371/journal.pgen.1009192 Brittany A. Martínez , Rosalie G. Hoyle , Scott Yeudall , Mitchell E. Granade , Thurl E. Harris , J. David Castle , Norbert Leitinger , Michelle L. Bland
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.
中文翻译:
果蝇中的先天性免疫信号通路将同化脂代谢从甘油三酸酯储存转变为磷脂合成以支持免疫功能。
在感染过程中,细胞资源被分配用于合成和分泌效应蛋白的中和代谢过程中,所述效应蛋白中和并杀死入侵的病原体。在果蝇中,这些效应子是在脂肪体内产生的抗菌肽(AMPs),该器官也充当主要的脂质储存库。在这里,我们询问幼虫脂肪体内Toll信号的激活如何扰动脂质稳态,以了解细胞如何满足免疫反应的代谢需求。我们发现,肥胖的身体收费信号,导致的遗传或生理激活甘油三酯存储组织自治减少是由DGAT同源的下降转录水平平行中途,该步骤执行甘油三酸酯合成的最后步骤。相反,诱导了合成膜磷脂的肯尼迪途径酶。质谱分析显示,具有活跃Toll信号的脂肪体内主要磷脂酰胆碱和磷脂酰乙醇胺种类的水平升高。内质网应激介质Xbp1有助于肯尼迪途径酶的Toll依赖性诱导,该酶因删除AMP基因而变得迟钝,从而减少了由Toll激活引起的分泌需求。与ER应激诱导一致,通过透射电子显微镜确定,具有活跃的Toll信号传导的脂肪细胞中的ER体积增加。减少的肯尼迪途径诱导的主要功能后果是对细菌感染的免疫反应受损。