The Drosophila IAP protein, DIAP2, is a key mediator of NF-kappaB signalling and is required for immune activation, both locally in the intestinal epithelia and during systemic, fat body-induced responses. We have found that transgenic expression of DIAP2 induces inflammation in the intestine, but not in the fat body, indicating a need for regulating DIAP2 in microbiotic environments. We describe the Drosophila caspase drICE, a known interaction partner of DIAP2, as a regulator of DIAP2 and NF-kappaB signalling in the intestinal epithelium. drICE acts by cleaving, and interfering with DIAP2s ability to ubiquitinate and, thereby, activate mediators of the NF-kappaB pathway. The drICE-cleaved form of DIAP2 is, moreover, unable to induce inflammation during basal conditions in the intestine. Interestingly, cleavage of DIAP2 does not interfere with pathogen-induced signalling, suggesting that drICE protects from immune responses induced by resident microbes. Accordingly, the negative regulatory effect of drICE is lost when rearing flies axenic. Hence, we show that drICE halts unwanted inflammatory signalling in the intestine by forming an inhibitory complex with DIAP2, interfering with the ability of DIAP2 to induce downstream signalling and NF-kappaB target gene activation.

中文翻译：

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drICE抑制DIAP2介导的炎症信号和肠道炎症

果蝇IAP蛋白DIAP2是NF-κB信号传导的关键介质，是肠道上皮局部以及全身性，脂肪体诱导的反应期间免疫激活所必需的。我们已经发现，DIAP2的转基因表达在肠道中引起了炎症，但在脂肪体内却没有，这表明在微生物环境中需要调节DIAP2。我们描述果蝇胱天蛋白酶drICE，DIAP2的已知的相互作用的伙伴，作为肠上皮中的DIAP2和NF-kappaB信号的调节剂。drICE的作用是切割并干扰DIAP2泛素化的能力，从而激活NF-κB途径的介质。此外，drICE切割的DIAP2形式在肠道基础条件下无法诱发炎症。有趣的是 DIAP2的裂解不会干扰病原体诱导的信号传导，这表明drICE可以防止驻留微生物诱导的免疫反应。因此，当饲养果蝇轴突时，drICE的负调节作用消失了。因此，我们显示drICE通过与DIAP2形成抑制复合物来阻止肠道中有害的炎症信号传导，从而干扰DIAP2诱导下游信号传导和NF-κB靶基因激活的能力。