Institute for Genetics and Cologne Excellence Cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Mol Cell Biol. 2012 Oct;32(19):3949-62. doi: 10.1128/MCB.00429-12. Epub 2012 Jul 30.
Integration of metabolic and immune responses during animal development ensures energy balance, permitting both growth and defense. Disturbed homeostasis causes organ failure, growth retardation, and metabolic disorders. Here, we show that the Drosophila melanogaster activating transcription factor 3 (Atf3) safeguards metabolic and immune system homeostasis. Loss of Atf3 results in chronic inflammation and starvation responses mounted primarily by the larval gut epithelium, while the fat body suffers lipid overload, causing energy imbalance and death. Hyperactive proinflammatory and stress signaling through NF-κB/Relish, Jun N-terminal kinase, and FOXO in atf3 mutants deregulates genes important for immune defense, digestion, and lipid metabolism. Reducing the dose of either FOXO or Relish normalizes both lipid metabolism and gene expression in atf3 mutants. The function of Atf3 is conserved, as human ATF3 averts some of the Drosophila mutant phenotypes, improving their survival. The single Drosophila Atf3 may incorporate the diversified roles of two related mammalian proteins.
动物发育过程中代谢和免疫反应的整合确保了能量平衡，从而促进生长和防御。内稳态失调会导致器官衰竭、生长迟缓以及代谢紊乱。在这里，我们发现果蝇激活转录因子 3 (Atf3) 可保护代谢和免疫系统的内稳态。Atf3 的缺失会导致主要由幼虫肠道上皮细胞引发的慢性炎症和饥饿反应，而脂肪体则会遭受脂质过载，导致能量失衡和死亡。NF-κB/Relish、Jun N-末端激酶和 FOXO 的过度活跃的促炎和应激信号在 atf3 突变体中会使免疫防御、消化和脂质代谢的重要基因失活。减少 FOXO 或 Relish 的剂量均可使 atf3 突变体中的脂质代谢和基因表达正常化。Atf3 的功能是保守的，因为人类 ATF3 可以避免一些果蝇突变体的表型，从而提高它们的存活率。单个果蝇 Atf3 可能整合了两种相关的哺乳动物蛋白的多样化功能。
