Inhibition of a NF-κB/Diap1 Pathway by PGRP-LF Is Required for Proper Apoptosis during <i>Drosophila</i> Development

NF-κB pathways are key signaling cascades of the Drosophila innate immune response. One of them, the Immune Deficiency (IMD) pathway, is under a very tight negative control. Although molecular brakes exist at each step of this signaling module from ligand availability to transcriptional regulation, it remains unknown whether repressors act in the same cells or tissues and if not, what is rationale behind this spatial specificity. We show here that the negative regulator of IMD pathway PGRP-LF is epressed in ectodermal derivatives. We provide evidence that, in the absence of any immune elicitor, PGRP-LF loss-of-function mutants, display a constitutive NF-κB/IMD activation specifically in ectodermal tissues leading to genitalia and tergite malformations. In agreement with previous data showing that proper development of these structures requires induction of apoptosis, we show that ectopic activation of NF-κB/IMD signaling leads to apoptosis inhibition in both genitalia and tergite primordia. We demonstrate that NF-κB/IMD signaling antagonizes apoptosis by up-regulating expression of the anti-apoptotic protein Diap1. Altogether these results show that, in the complete absence of infection, the negative regulation of NF-κB/IMD pathway by PGRP-LF is crucial to ensure proper induction of apoptosis and consequently normal fly development. These results highlight that IMD pathway regulation is controlled independently in different tissues, probably reflecting the different roles of this signaling cascade in both developmental and immune processes.核因子κB（NF-κB）信号通路是果蝇先天免疫应答的关键信号级联反应。其中一条通路即免疫缺陷（IMD）信号通路，受到极其严格的负调控。尽管从配体可用性到转录调控的该信号模块的每一个环节均存在分子刹车（负调控因子），但目前仍不清楚这些阻遏因子是否作用于同一细胞或组织；若并非如此，则这种空间特异性背后的分子机制是什么。我们在此证实，IMD通路的负调控因子PGRP-LF仅在外胚层衍生物中表达。我们提供的证据表明，在无任何免疫激发子的情况下，PGRP-LF功能丧失突变体的外胚层组织中会出现组成型NF-κB/IMD激活，进而导致生殖器与背板畸形。与此前关于这些结构的正常发育依赖细胞凋亡诱导的研究结果一致，我们证实NF-κB/IMD信号的异位激活会抑制生殖器原基与背板原基中的细胞凋亡。我们进一步证明，NF-κB/IMD信号可通过上调抗凋亡蛋白Diap1的表达来拮抗细胞凋亡。综上，上述结果表明，在完全无感染的状态下，PGRP-LF对NF-κB/IMD通路的负调控对于确保细胞凋亡的正常诱导、进而保障果蝇的正常发育至关重要。这些结果同时揭示，IMD通路的调控在不同组织中独立进行，这或许反映了该信号级联在发育与免疫过程中的不同功能。