Centre for the Molecular and Cellular Biology of Inflammation and Peter Gorer Department of Immunobiology, King's College London School of Medicine, London SE1 1UL, UK; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell. 2013 Oct 10;155(2):435-47. doi: 10.1016/j.cell.2013.09.007. Epub 2013 Sep 26.
Infections disturb metabolic homeostasis in many contexts, but the underlying connections are not completely understood. To address this, we use paired genetic and computational screens in Drosophila to identify transcriptional regulators of immunity and pathology and their associated target genes and physiologies. We show that Mef2 is required in the fat body for anabolic function and the immune response. Using genetic and biochemical approaches, we find that MEF2 is phosphorylated at a conserved site in healthy flies and promotes expression of lipogenic and glycogenic enzymes. Upon infection, this phosphorylation is lost, and the activity of MEF2 changes--MEF2 now associates with the TATA binding protein to bind a distinct TATA box sequence and promote antimicrobial peptide expression. The loss of phosphorylated MEF2 contributes to loss of anabolic enzyme expression in Gram-negative bacterial infection. MEF2 is thus a critical transcriptional switch in the adult fat body between metabolism and immunity.
在许多情况下，感染会扰乱代谢稳态，但其中的潜在联系尚不完全清楚。为了解决这个问题，我们使用果蝇的基因和计算双筛，来鉴定免疫和病理相关的转录调控因子及其靶基因和生理功能。我们发现，Mef2 在脂肪体中对于合成代谢功能和免疫反应是必需的。通过遗传和生化方法，我们发现 MEF2 在健康的果蝇中在一个保守位点发生磷酸化，并促进脂肪生成和糖生成酶的表达。在感染时，这种磷酸化会丢失，而 MEF2 的活性发生改变——MEF2 现在与 TATA 结合蛋白结合，结合一个不同的 TATA 框序列，并促进抗菌肽的表达。磷酸化 MEF2 的丢失导致革兰氏阴性菌感染时合成代谢酶表达的丧失。因此，MEF2 是成年脂肪体在代谢和免疫之间的关键转录开关。
