The Taiman Transcriptional Coactivator Engages Toll Signals to Promote Apoptosis and Intertissue Invasion in Drosophila
The Taiman Transcriptional Coactivator Engages Toll Signals to Promote Apoptosis and Intertissue Invasion in Drosophila
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DOI：
10.1016/j.cub.2019.07.012
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发表时间：
2019-09-09
期刊：
影响因子：
9.2
通讯作者：
Moberg, Ken
中科院分区：
文献类型：
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作者：
Byun, Phil K.;Zhang, Can;Moberg, Ken
果蝇Taiman(TAI)蛋白与人类类固醇受体辅活化子SRC1-3同源，与20-羟基蜕皮酮(20E)受体(ECR)形成复合体，激活转录。TAI通过与ECR和辅活化约克(YKI)的相互作用，在肠道内稳态、生殖系维持、细胞运动和增殖中发挥作用。TAI还促进肿瘤细胞对邻近器官的侵袭，但这种促进侵袭的机制尚不清楚。在这里，我们表明，TAI的表达将无柄的蛹翅细胞转化为侵袭性的团块，在20E高峰期渗透到邻近的胸腔。候选分析证实依赖于20E和河马途径的元件，如yki和yki-tai靶标Dilp8。对TAI诱导的翼转录组进行筛选，可以检测到天然免疫因子的丰富，包括Spatzle(SPZ)家族分泌的Toll配体，在细胞竞争中诱导细胞凋亡。表达TAI的WING细胞诱导相邻胸腺细胞间的免疫信号和细胞凋亡，SPZ、Toll或RPR/HID/GRIM促凋亡因子的基因减少均可抑制侵袭，提示细胞间SPZ-Toll回路支持杀伤介导的侵袭。在幼虫上皮中对这些相互作用进行建模证实，TAI通过涉及Toll、SPZ因子和SPZ抑制剂坏死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，IMD途径与Toll平行操作，控制核因子kappaB(NF-kappa B)活性，并独立调节JNK活性。综上所述，这些发现表明TAI通过SPZ-Toll促进竞争性细胞杀伤，这种杀伤机制支持果蝇的病理性组织间侵袭。
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 Spatzle (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 kappa B (NF-kappa B) 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.