Activating transcription factor 3 regulates immune and metabolic homeostasis. Drosophila melanogaster

Integration of metabolic, stress and immune responses plays a fundamental role during animal development to maintain energy homeostasis while ensuring growth and proper developmental timing. Perturbation of metabolic and immune signaling circuits has detrimental consequences to animal development including growth retardation, organ malfunction and emergence of the metabolic syndrome. Here, we demonstrate that the Drosophila basic region-leucine zipper (bZIP) protein, Activating transcription factor 3 (Atf3), safeguards a balance of metabolic and immune system responses during fly development. Loss of Atf3 function results in lethality during late-larval and pupal stages. Atf3-deficient larvae exhibit phenotypes resembling the metabolic syndrome in mammals. Excessive accumulation of lipids in the larval fat body and gut is accompanied by altered expression of genes involved in lipid metabolism. Moreover, the fat body of atf3 mutants becomes infiltrated by hemocytes. The major pro-inflammatory pathways signaling through JNK and Imd are hyperactivated in atf3 mutants, causing ectopic expression of antimicrobial peptide genes. Suppression of the immune response, achieved by reducing the gene dose of the transcription factors FOXO or NF-kappaB/Relish, significantly improves lipid metabolism and normalizes gene expression profile of atf3 mutants. In addition, heterozygosity of relish partially rescues lethality of the atf3 mutants. Our data thus identify Atf3 as an essential player that links metabolic and immune system homeostasis during animal development. Overall design: Examination of mRNA levels from four genotypes of male, 3rd instar Drosophila melanogaster larvae. mRNA levels from four genotypes relative to y w control were determined using two biological replicates per genotype. Genome build: BDGP R5/dm3, April 2006

代谢、应激与免疫应答的协同调控在动物发育过程中发挥核心作用，既可维持能量稳态，又能保障个体生长与正常发育时序。代谢与免疫信号环路的紊乱会对动物发育产生不利影响，包括生长迟缓、器官功能异常以及代谢综合征的发生。本研究证实，果蝇（Drosophila）碱性亮氨酸拉链（basic region-leucine zipper，bZIP）家族蛋白激活转录因子3（Activating transcription factor 3，Atf3）在果蝇发育过程中维持代谢与免疫应答的平衡。Atf3功能缺失会导致果蝇在幼虫晚期和蛹期死亡。Atf3缺陷型幼虫会表现出类似哺乳动物代谢综合征的表型。幼虫脂肪体与肠道内出现脂质过度蓄积，同时参与脂质代谢的基因表达发生改变。此外，atf3突变体的脂肪体还会出现血细胞浸润现象。通过c-Jun氨基末端激酶（JNK）与免疫缺陷（Imd）通路转导信号的主要促炎通路在atf3突变体中被过度激活，进而引发抗菌肽基因的异位表达。通过降低转录因子FOXO或核因子κB/Relish（NF-kappaB/Relish）的基因剂量来抑制免疫应答，可显著改善atf3突变体的脂质代谢，并使其基因表达谱恢复正常。此外，relish基因的杂合突变可部分挽救atf3突变体的致死表型。综上，本研究数据证实Atf3是连接动物发育过程中代谢与免疫稳态的关键调控因子。实验设计：对四种基因型的雄性三龄黑腹果蝇（Drosophila melanogaster）幼虫的mRNA水平进行检测。以y w品系为对照，通过每个基因型设置两个生物学重复，测定四种基因型的mRNA相对表达水平。基因组组装版本：BDGP R5/dm3，2006年4月发布。