The Drosophila TNF Eiger activates caspase-dependent necrosis when apoptosis is blocked
The Drosophila TNF Eiger activates caspase-dependent necrosis when apoptosis is blocked
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DOI：
10.1101/304964
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Mingli Li;Yun Fan
中科院分区：
文献类型：
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作者：
Mingli Li;Yun Fan
艾格蛋白（Egr）是哺乳动物肿瘤坏死因子（TNF）的同源物，是果蝇c-Jun n -末端激酶（JNK）应激反应信号通路的配体。虽然Egr的表达经常导致细胞凋亡，但它也与非凋亡细胞死亡的激活有关。然而，目前尚不清楚Egr如何诱导细胞凋亡和非凋亡细胞死亡，如果是这样，这些过程是如何协调的。本研究表明，Egr在发育中的果蝇眼中表达可诱导细胞凋亡和非凋亡性发育缺陷，这两种缺陷都依赖于jnk。有趣的是，当凋亡效应caspase DrICE和Dcp-1缺陷或抑制时，Egr的表达诱导坏死，其特征是细胞膜完整性丧失、细胞质半透明和细胞器聚集。令人惊讶的是，坏死的诱导依赖于启动物caspase Dronc的催化活性和JNK信号的输入，而不依赖于它们在细胞凋亡中的作用。因此，与哺乳动物caspase-8类似，果蝇中的caspase也具有促进tnf介导的细胞凋亡和抑制坏死的双重作用。
Eiger (Egr), the homolog of the mammalian tumor-necrosis factor (TNF), is the ligand of the c-Jun N-terminal kinase (JNK) stress response signaling pathway in Drosophila. Although expression of Egr frequently leads to apoptosis, it has also been implicated in activation of non-apoptotic cell death. However, it is not yet clear how Egr can induce both apoptosis and non-apoptotic cell death, and if so, how such processes are coordinated. Here, we show that expression of Egr in the developing Drosophila eye induces apoptosis and non-apoptotic developmental defects, both of which are JNK-dependent. Intriguingly, when apoptotic effector caspases DrICE and Dcp-1 are defective or inhibited, expression of Egr induces necrosis characterized by loss of cell membrane integrity, translucent cytoplasm and aggregation of cellular organelles. Surprisingly, the induction of necrosis depends on the catalytic activity of the initiator caspase Dronc and the input from JNK signaling independently of their roles in apoptosis. Therefore, similar to the mammalian caspase-8, caspases in Drosophila also have dual roles in promoting TNF-mediated apoptosis and inhibiting necrosis.