Institut National de la Santé et de la Recherche Médicale Equipe Avenir, 67084 Strasbourg, France.
Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10717-22. doi: 10.1073/pnas.1304380110. Epub 2013 Jun 7.
The Drosophila defense against pathogens largely relies on the activation of two signaling pathways: immune deficiency (IMD) and Toll. The IMD pathway is triggered mainly by Gram-negative bacteria, whereas the Toll pathway responds predominantly to Gram-positive bacteria and fungi. The activation of these pathways leads to the rapid induction of numerous NF-κB-induced immune response genes, including antimicrobial peptide genes. The IMD pathway shows significant similarities with the TNF receptor pathway. Recent evidence indicates that the IMD pathway is also activated in response to various noninfectious stimuli (i.e., inflammatory-like reactions). To gain a better understanding of the molecular machinery underlying the pleiotropic functions of this pathway, we first performed a comprehensive proteomics analysis to identify the proteins interacting with the 11 canonical members of the pathway initially identified by genetic studies. We identified 369 interacting proteins (corresponding to 291 genes) in heat-killed Escherichia coli-stimulated Drosophila S2 cells, 92% of which have human orthologs. A comparative analysis of gene ontology from fly or human gene annotation databases points to four significant common categories: (i) the NuA4, nucleosome acetyltransferase of H4, histone acetyltransferase complex, (ii) the switching defective/sucrose nonfermenting-type chromatin remodeling complex, (iii) transcription coactivator activity, and (iv) translation factor activity. Here we demonstrate that sumoylation of the IκB kinase homolog immune response-deficient 5 plays an important role in the induction of antimicrobial peptide genes through a highly conserved sumoylation consensus site during bacterial challenge. Taken together, the proteomics data presented here provide a unique avenue for a comparative functional analysis of proteins involved in innate immune reactions in flies and mammals.
免疫缺陷（IMD）和 Toll。IMD 通路主要由革兰氏阴性菌触发，而 Toll 通路主要对革兰氏阳性菌和真菌做出响应。这些通路的激活会导致大量 NF-κB 诱导的免疫反应基因，包括抗菌肽基因的迅速诱导。IMD 通路与 TNF 受体通路有显著的相似性。最近的证据表明，IMD 通路也会对各种非传染性刺激（即炎症样反应）做出响应。为了更好地理解该通路的多效性功能的分子机制，我们首先进行了一项全面的蛋白质组学分析，以鉴定最初通过遗传研究鉴定的该通路的 11 个经典成员相互作用的蛋白质。我们在热灭活的大肠杆菌刺激的果蝇 S2 细胞中鉴定出 369 个相互作用的蛋白质（对应于 291 个基因），其中 92%具有人类同源物。来自果蝇或人类基因注释数据库的基因本体比较分析指出了四个显著的共同类别：（i）NuA4，H4 核小体乙酰转移酶，组蛋白乙酰转移酶复合物；（ii）切换缺陷/蔗糖非发酵型染色质重塑复合物；（iii）转录共激活因子活性；（iv）翻译因子活性。这里我们证明，在细菌攻击过程中，IκB 激酶同源物免疫反应缺陷 5 的 SUMO 化在抗菌肽基因的诱导中起着重要作用，这是通过一个高度保守的 SUMO 化共识位点实现的。总之，这里呈现的蛋白质组学数据为比较分析果蝇和哺乳动物中参与先天免疫反应的蛋白质的功能提供了一条独特的途径。
