The Drosophila IAP protein, Diap2, is a key mediator of NF-κB signalling and innate immune responses. Diap2 is required for both local immune activation, taking place in the epithelial cells of the gut and trachea, and for mounting systemic immune responses in the cells of the fat body. We have found that transgenic expression of Diap2 leads to a spontaneous induction of NF-κB target genes, inducing chronic inflammation in the Drosophila midgut, but not in the fat body. Drice is a Drosophila effector caspase known to interact and form a stable complex with Diap2. We have found that this complex formation induces its subsequent degradation, thereby regulating the amount of Diap2 driving NF-κB signalling in the intestine. Concordantly, loss of Drice activity leads to accumulation of Diap2 and to chronic intestinal inflammation. Interestingly, Drice does not interfere with pathogen-induced signalling, suggesting that it protects from immune responses induced by resident microbes. Accordingly, no inflammation was detected in transgenic Diap2 flies and Drice-mutant flies reared in axenic conditions. Hence, we show that Drice, by restraining Diap2, halts unwanted inflammatory signalling in the intestine.

果蝇IAP 蛋白 Diap2 是 NF-κB 信号和先天免疫反应的关键介质。Diap2 是发生在肠道和气管上皮细胞中的局部免疫激活以及在脂肪体细胞中建立全身免疫反应所必需的。我们发现 Diap2 的转基因表达会导致 NF-κB 靶基因的自发诱导，从而在果蝇中肠而非脂肪体中诱导慢性炎症。Drice 是果蝇已知与 Diap2 相互作用并形成稳定复合物的效应半胱天冬酶。我们发现这种复合物的形成会诱导其随后的降解，从而调节驱动肠道中 NF-κB 信号的 Diap2 的数量。一致地，Drice 活性的丧失导致 Diap2 的积累和慢性肠道炎症。有趣的是，Drice 不会干扰病原体诱导的信号传导，这表明它可以防止常驻微生物诱导的免疫反应。因此，在无菌条件下饲养的转基因 Diap2 果蝇和 Drice 突变果蝇中未检测到炎症。因此，我们表明 Drice 通过抑制 Diap2 阻止了肠道中不需要的炎症信号。