Spatially Restricted Regulation of Spätzle/Toll Signaling during Cell Competition.
Spatially Restricted Regulation of Spätzle/Toll Signaling during Cell Competition.
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DOI：
10.1016/j.devcel.2018.08.001
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发表时间：
2018-09-24
影响因子：
11.8
通讯作者：
Johnston LA
中科院分区：
文献类型：
--
作者：
Alpar L;Bergantiños C;Johnston LA
细胞竞争利用适应性的比较来选择性地消除被认为不太健康的细胞。在果蝇中，由Toll配体Spätzle（Spz）、几种Toll相关受体和NF κ B因子组成的信号模块诱导较弱的“失败者”细胞从生长的翼盘中凋亡消除。这个模块是如何被激活和限制竞争的椎间盘细胞是未知的。在这里，我们使用Myc诱导的细胞竞争，以证明失败者细胞消除需要本地，翼盘合成Spz。我们确定了Spz加工酶（SPE）和模块化丝氨酸蛋白酶（ModSP）作为Spz调节的竞争性信号传导的激活剂，并表明“赢家”细胞通过促进SPE的产生来触发附近WT细胞的消除。此外，Spz需要Toll和Toll-8来诱导翅盘细胞凋亡。因此，在细胞竞争过程中，Spz介导的信号传导被严格限制在成虫盘上，允许在不损害生物体生理学的情况下纠正组织适应性的错误。低水平的Toll配体Spätzle及其活化蛋白酶由翅盘细胞持续合成，但信号传导是无效的。Alpar等人表明，Myc超级竞争细胞促进蛋白酶的产生，从而触发Spätzle激活并诱导选择性消除附近野生型细胞的杀伤信号。
Cell competition employs comparisons of fitness to selectively eliminate cells sensed as less healthy. In Drosophila, apoptotic elimination of the weaker ‘loser’ cells from growing wing discs is induced by a signaling module consisting of the Toll ligand Spätzle (Spz), several Toll related receptors and NFkB factors. How this module is activated and restricted to competing disc cells is unknown. Here, we use Myc-induced cell competition to demonstrate that loser cell elimination requires local, wing disc synthesis of Spz. We identify Spz Processing Enzyme (SPE) and Modular Serine Protease (ModSP) as activators of Spz-regulated competitive signaling, and show that ‘winner’ cells trigger elimination of nearby WT cells by boosting SPE production. Moreover, Spz requires both Toll and Toll-8 to induce apoptosis of wing disc cells. Thus, during cell competition, Spz-mediated signaling is strictly confined to the imaginal disc, allowing errors in tissue fitness to be corrected without compromising organismal physiology. Low levels of the Toll ligand Spätzle and its activating proteases are synthesized continuously by wing disc cells, but signaling is unproductive. Alpar et al. show that Myc super-competitor cells boost production of the proteases, thereby triggering Spätzle activation and inducing a killing signal that selectively eliminates nearby wild-type cells.
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