Wu L P, Anderson K V
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Nature. 1998 Mar 5;392(6671):93-7. doi: 10.1038/32195.
The Drosophila immune response uses many of the same components as the mammalian innate immune response, including signalling pathways that activate transcription factors of the Rel/NK-kappaB family. In response to infection, two Rel proteins, Dif and Dorsal, translocate from the cytoplasm to the nuclei of larval fat-body cells. The Toll signalling pathway, which controls dorsal-ventral patterning during Drosophila embryogenesis, regulates the nuclear import of Dorsal in the immune response, but here we show that the Toll pathway is not required for nuclear import of Dif. Cytoplasmic retention of both Dorsal and Dif depends on Cactus protein; nuclear import of Dorsal and Dif is accompanied by degradation of Cactus. Therefore the two signalling pathways that target Cactus for degradation must discriminate between Cactus-Dorsal and Cactus-Dif complexes. We identified new genes that are required for normal induction of transcription of an antibacterial peptide during the immune response. Mutations in three of these genes prevent nuclear import of Dif in response to infection, and define new components of signalling pathways involving Rel. Mutations in three other genes cause constitutive nuclear localization of Dif; these mutations may block Rel protein activity by a novel mechanism.
果蝇的免疫反应使用了许多与哺乳动物先天免疫反应相同的成分，包括激活Rel/NK-κB家族转录因子的信号通路。在受到感染时，两种Rel蛋白，即Dif和Dorsal，从细胞质转移到幼虫脂肪体细胞的细胞核中。Toll信号通路在果蝇胚胎发育过程中控制背腹模式形成，在免疫反应中调节Dorsal的核输入，但我们在此表明，Toll通路对于Dif的核输入并非必需。Dorsal和Dif在细胞质中的滞留取决于Cactus蛋白；Dorsal和Dif的核输入伴随着Cactus的降解。因此，两条靶向Cactus进行降解的信号通路必须区分Cactus-Dorsal和Cactus-Dif复合物。我们鉴定出了免疫反应期间正常诱导抗菌肽转录所需的新基因。其中三个基因的突变会阻止感染时Dif的核输入，并定义了涉及Rel的信号通路的新成分。另外三个基因的突变导致Dif的组成型核定位；这些突变可能通过一种新机制阻断Rel蛋白的活性。
