Cardoso Maira Arruda, Fontenele Marcio, Lim Bomyi, Bisch Paulo Mascarello, Shvartsman Stanislav Y, Araujo Helena Marcolla
Instituto de Ciências Biomédicas, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
Development. 2017 Aug 15;144(16):2907-2913. doi: 10.1242/dev.145557. Epub 2017 Jul 13.
The evolutionarily conserved Toll signaling pathway controls innate immunity across phyla and embryonic patterning in insects. In the embryo, Toll is required to establish gene expression domains along the dorsal-ventral axis. Pathway activation induces degradation of the IκB inhibitor Cactus, resulting in a ventral-to-dorsal nuclear gradient of the NFκB effector Dorsal. Here, we investigate how modulates Toll signals through its effects on the Dorsal gradient and on Dorsal target genes. Quantitative analysis using a series of loss- and gain-of-function conditions shows that the ventral and lateral aspects of the Dorsal gradient can behave differently with respect to Cactus fluctuations. In lateral and dorsal embryo domains, loss of Cactus allows more Dorsal to translocate to the nucleus. Unexpectedly, loss-of-function alleles decrease Dorsal nuclear localization ventrally, where Toll signals are high. Overexpression analysis suggests that this ability of Cactus to enhance Toll stems from the mobilization of a free Cactus pool induced by the Calpain A protease. These results indicate that Cactus acts to bolster Dorsal activation, in addition to its role as a NFκB inhibitor, ensuring a correct response to Toll signals.
进化上保守的Toll信号通路控制着跨门的先天免疫以及昆虫的胚胎模式形成。在胚胎中，Toll对于沿背腹轴建立基因表达结构域是必需的。通路激活会诱导IκB抑制剂Cactus的降解，导致NFκB效应因子Dorsal从腹侧到背侧的核梯度。在此，我们研究了 如何通过其对Dorsal梯度和Dorsal靶基因的影响来调节Toll信号。使用一系列功能丧失和功能获得条件进行的定量分析表明，Dorsal梯度的腹侧和外侧方面在Cactus波动方面可能表现不同。在胚胎的外侧和背侧区域，Cactus的缺失会使更多的Dorsal转运到细胞核。出乎意料的是，功能丧失等位基因会降低腹侧Dorsal的核定位，而腹侧的Toll信号很高。过表达分析表明，Cactus增强Toll的这种能力源于钙蛋白酶A蛋白酶诱导的游离Cactus池的动员。这些结果表明，Cactus除了作为NFκB抑制剂的作用外，还起到增强Dorsal激活的作用，确保对Toll信号作出正确反应。
