Dronc-independent basal executioner caspase activity sustains Drosophila imaginal tissue growth
Dronc-independent basal executioner caspase activity sustains Drosophila imaginal tissue growth
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DOI：
10.1073/pnas.1904647116
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发表时间：
2019-09
影响因子：
11.1
通讯作者：
Natsuki Shinoda;Nozomi Hanawa;T. Chihara;A. Koto;M. Miura
中科院分区：
文献类型：
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作者：
Natsuki Shinoda;Nozomi Hanawa;T. Chihara;A. Koto;M. Miura
Caspase是参与细胞死亡的酶，其通过凋亡激活被认为代表了不可逆的细胞破坏。此外，越来越多的证据表明caspase在细胞凋亡之外的功能越来越多样化。本研究以果蝇翅膀为模型，揭示了特定的刽子手半胱天冬酶Dcp-1和Decay通过诱导细胞凋亡促进而不是抑制组织生长。这些刽子手caspase独立于启动者caspase Dronc和细胞凋亡起作用。我们进一步表明caspase介导的Acinus分裂对维持组织生长很重要。我们的研究强调了刽子手caspase介导的底物基础蛋白水解裂解在组织生长过程中的重要性，研究结果暗示了caspase的原始功能——不是凋亡，而是基础蛋白水解裂解对细胞活力的影响。Caspase是一种参与程序性细胞死亡的酶，在多细胞生物中是保守的。除了在细胞死亡中发挥作用外，caspase在广泛的细胞功能中作为一种不可或缺的酶而出现，这些功能最近被称为caspase依赖性非致死细胞过程（CDPs）。在这项研究中，我们以果蝇的翅膀为模型，研究了细胞死亡信号在组织大小决定中的作用。我们发现果蝇刽子手的半胱天冬酶Dcp-1和Decay，而不是Drice，独立于细胞凋亡促进翅膀生长。大多数关于CDPs的报道都强调了caspase （Dronc）的时空调控的重要性；然而，这种亚致死caspase的功能与Dronc无关，这表明CDP的调节机制更为多样化。TurboID是一种改进的混杂生物素连接酶，可以将邻近的蛋白质生物素化，标记到半胱天冬酶的C端，揭示了刽子手半胱天冬酶的邻居之间的差异。此外，我们还发现刽子手半胱天冬酶的底物Acinus的裂解在促进翅膀生长中起重要作用。这些结果证明了刽子手caspase介导的底物基础蛋白水解裂解在维持组织生长中的重要性。考虑到在单细胞藻类中存在类似caspase的DEVDase活性，我们的研究结果可能强调了caspase的原始功能——不是细胞死亡，而是基础蛋白水解裂解细胞活力。
Significance Caspase is the enzyme involved in cell death, and its activation via the apoptosome is thought to represent irreversible cellular destruction. Furthermore, accumulating evidence suggests increasingly diverse functions of caspase beyond apoptosis. Here, using Drosophila wing as a model, we reveal that the specific executioner caspases, Dcp-1 and Decay, promote, rather than suppress by inducing apoptosis, tissue growth. These executioner caspases act independently of initiator caspase Dronc and apoptosis. We further show that the caspase-mediated cleavage of Acinus is important for sustaining tissue growth. Our research highlights the importance of executioner caspase-mediated basal proteolytic cleavage of substrates during tissue growth, and the findings hint at the original function of caspase—not apoptosis, but basal proteolytic cleavages for cell vigor. Caspase is best known as an enzyme involved in programmed cell death, which is conserved among multicellular organisms. In addition to its role in cell death, caspase is emerging as an indispensable enzyme in a wide range of cellular functions, which have recently been termed caspase-dependent nonlethal cellular processes (CDPs). In this study, we examined the involvement of cell death signaling in tissue-size determination using Drosophila wing as a model. We found that the Drosophila executioner caspases Dcp-1 and Decay, but not Drice, promoted wing growth independently of apoptosis. Most of the reports on CDPs argue the importance of the spatiotemporal regulation of the initiator caspase, Dronc; however, this sublethal caspase function was independent of Dronc, suggesting a more diverse array of CDP regulatory mechanisms. Tagging of TurboID, an improved promiscuous biotin ligase that biotinylates neighboring proteins, to the C terminus of caspases revealed the differences among the neighbors of executioner caspases. Furthermore, we found that the cleavage of Acinus, a substrate of the executioner caspase, was important in promoting wing growth. These results demonstrate the importance of executioner caspase-mediated basal proteolytic cleavage of substrates in sustaining tissue growth. Given the existence of caspase-like DEVDase activity in a unicellular alga, our results likely highlight the original function of caspase—not cell death, but basal proteolytic cleavages for cell vigor.