Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Curr Biol. 2019 Sep 9;29(17):2790-2800.e4. doi: 10.1016/j.cub.2019.07.012. Epub 2019 Aug 8.
The Drosophila Taiman (Tai) protein is homologous to the human steroid-receptor coactivators SRC1-3 and activates transcription in complex with the 20-hydroxyecdysone (20E) receptor (EcR). Tai has roles in intestinal homeostasis, germline maintenance, cell motility, and proliferation through interactions with EcR and the coactivator Yorkie (Yki). Tai also promotes invasion of tumor cells in adjacent organs, but this pro-invasive mechanism is undefined. Here, we show that Tai expression transforms sessile pupal wing cells into an invasive mass that penetrates the adjacent thorax during a period of high 20E. Candidate analysis confirms a reliance on elements of the 20E and Hippo pathways, such as Yki and the Yki-Tai target dilp8. Screening the Tai-induced wing transcriptome detects enrichment for innate immune factors, including the Spätzle (Spz) family of secreted Toll ligands that induce apoptosis during cell competition. Tai-expressing wing cells induce immune signaling and apoptosis among adjacent thoracic cells, and genetic reduction of spz, Toll, or the rpr/hid/grim pro-apoptotic factors each suppresses invasion, suggesting an intercellular Spz-Toll circuit supports killing-mediated invasion. Modeling these interactions in larval epithelia confirms that Tai kills neighboring cells via a mechanism involving Toll, Spz factors, and the Spz inhibitor Necrotic. Tai-expressing cells evade death signals by repressing the immune deficiency (IMD) pathway, which operates in parallel to Toll to control nuclear factor κB (NF-κB) activity and independently regulates JNK activity. In sum, these findings suggest that Tai promotes competitive cell killing via Spz-Toll and that this killing mechanism supports pathologic intertissue invasion in Drosophila.
果蝇 Taiman（Tai）蛋白与人类类固醇受体共激活因子 SRC1-3 同源，与 20-羟基蜕皮激素（20E）受体（EcR）结合激活转录。Tai 通过与 EcR 和共激活因子 Yorkie（Yki）相互作用，在肠道稳态、生殖细胞维持、细胞运动和增殖中发挥作用。Tai 还促进相邻器官肿瘤细胞的侵袭，但这种促侵袭机制尚不清楚。在这里，我们表明，在 20E 水平高的时期，Tai 的表达将静止的蛹翅细胞转化为侵袭性肿块，穿透相邻的胸腔。候选分析证实依赖于 20E 和 Hippo 途径的元件，如 Yki 和 Yki-Tai 靶标 dilp8。筛选 Tai 诱导的翅转录组检测到先天免疫因子的富集，包括分泌 Toll 配体的 Spätzle（Spz）家族，该家族在细胞竞争过程中诱导细胞凋亡。表达 Tai 的翅细胞诱导相邻胸细胞的免疫信号和凋亡，并且 spz、Toll 或 rpr/hid/grim 促凋亡因子的遗传减少均抑制侵袭，表明细胞间 Spz-Toll 回路支持杀伤介导的侵袭。在幼虫上皮细胞中模拟这些相互作用证实，Tai 通过涉及 Toll、Spz 因子和 Spz 抑制剂 Necrotic 的机制杀死邻近细胞。表达 Tai 的细胞通过抑制免疫缺陷（IMD）途径逃避死亡信号，该途径与 Toll 平行运作，以控制核因子 κB（NF-κB）活性，并独立调节 JNK 活性。总之，这些发现表明，Tai 通过 Spz-Toll 促进竞争细胞杀伤，并且这种杀伤机制支持果蝇中病理组织间侵袭。
