PgmNr D114: The Drosophila TNF Eiger activates Dronc-dependent necrosis when apoptosis is blocked.

Authors:
M. Li; Y. Fan


Institutes
School of Biosciences, University of Birmingham, Birmingham, United Kingdom.


Keyword: necrosis

Abstract:

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. For example, expression of Egr under the control of the eye-specific driver GMR (GMR>egr) results in a small eye phenotype which cannot be suppressed by P35, an inhibitor of the effector caspases DrICE and Dcp-1. Paradoxically, it has been reported that GMR>egr-induced eye ablation phenotype can be partially rescued by defective apoptosis through reduction of pro-apoptotic gene expression or inhibition of the initiator caspase Dronc. It is therefore not yet clear whether Egr can induce both apoptotic and non-apoptotic cell death, and if so, how such processes are coordinated. Here, we show that GMR>egr primarily induces apoptosis starting from the 3rd instar larval stage. Loss-of-function analysis reveals that such induction of apoptosis is through the canonical pathway and mainly mediated by the pro-apoptotic gene hid. Intriguingly, when apoptosis is blocked by expression of P35 (GMR>egr, p35), necrosis, indicated by Propidium Iodide labeling and Electron Microscopy, is induced that counteracts apoptotic inhibition by P35 resulting small eyes at the end. Moreover, loss one copy of Dronc, which does not affect GMR>egr-induced apoptosis, can suppress GMR>egr, p35-induced eye ablation phenotype suggesting different levels of Dronc are required for Egr-induced apoptosis and, if apoptosis is blocked, necrosis. As the mammalian TNF can activate the extrinsic apoptosis pathway and, if apoptosis is defective, triggers necrosis, our study suggests such a process is more conserved in Drosophila than previously thought.