Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, BioCity, Turku, Finland.
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
Cell Death Differ. 2022 Jan;29(1):28-39. doi: 10.1038/s41418-021-00832-w. Epub 2021 Jul 14.
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 信号转导和先天免疫反应的关键介质。Diap2 既需要在肠道和气管的上皮细胞中发生局部免疫激活，也需要在脂肪体的细胞中引发全身免疫反应。我们发现，Diap2 的转基因表达导致 NF-κB 靶基因的自发诱导，从而在果蝇中肠引起慢性炎症，但不在脂肪体中。Drice 是一种已知与 Diap2 相互作用并形成稳定复合物的果蝇效应半胱天冬酶。我们发现这种复合物的形成诱导其随后的降解，从而调节驱动 NF-κB 信号转导的 Diap2 的数量在肠道中。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 不干扰病原体诱导的信号转导，表明它可以防止由常驻微生物引起的免疫反应。相应地，在无菌条件下饲养的转基因 Diap2 蝇和 Drice 突变蝇中未检测到炎症。因此，我们表明 Drice 通过限制 Diap2 来阻止肠道中不需要的炎症信号转导。
