The PERK pathway independently triggers apoptosis and a Rac1/Slpr/JNK/Dilp8 signaling favoring tissue homeostasis in a chronic ER stress Drosophila model.
The PERK pathway independently triggers apoptosis and a Rac1/Slpr/JNK/Dilp8 signaling favoring tissue homeostasis in a chronic ER stress Drosophila model.
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DOI：
10.1038/cddis.2014.403
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发表时间：
2014-10-09
影响因子：
9
通讯作者：
Gaumer S
中科院分区：
文献类型：
--
作者：
Demay Y;Perochon J;Szuplewski S;Mignotte B;Gaumer S
内质网(ER)在蛋白质折叠中起着重要作用。内质网中未折叠蛋白的积累诱导了一种应激，这种应激可以通过未折叠蛋白反应(UPR)来解决。内质网应激的慢性化导致UPR诱导的细胞凋亡，进而导致组织动态平衡的失衡。尽管在许多毁灭性的人类疾病中观察到内质网应激依赖的细胞凋亡，但在慢性内质网应激后，细胞如何激活细胞凋亡和促进组织动态平衡仍然知之甚少。在这里，我们使用果蝇翅膀想象盘作为模型系统，在体内验证了早老素的过度表达诱导了慢性内质网应激。我们观察到，在这个新的慢性内质网应激模型中，依赖于PERK/ATF4的细胞凋亡需要下调抗细胞凋亡的DIAP1基因。PERK/ATF4还通过在凋亡细胞中激活rac1和slpr激活JNK通路，导致Dilp8的表达。这种胰岛素样肽导致发育延迟，这在一定程度上允许替换凋亡的细胞。由于一个新的慢性内质网应激模型，这些结果建立了一条新的途径，既参与组织动态平衡，又通过原始调节触发细胞凋亡。
The endoplasmic reticulum (ER) has a major role in protein folding. The accumulation of unfolded proteins in the ER induces a stress, which can be resolved by the unfolded protein response (UPR). Chronicity of ER stress leads to UPR-induced apoptosis and in turn to an unbalance of tissue homeostasis. Although ER stress-dependent apoptosis is observed in a great number of devastating human diseases, how cells activate apoptosis and promote tissue homeostasis after chronic ER stress remains poorly understood. Here, using the Drosophila wing imaginal disc as a model system, we validated that Presenilin overexpression induces chronic ER stress in vivo. We observed, in this novel model of chronic ER-stress, a PERK/ATF4-dependent apoptosis requiring downregulation of the antiapoptotic diap1 gene. PERK/ATF4 also activated the JNK pathway through Rac1 and Slpr activation in apoptotic cells, leading to the expression of Dilp8. This insulin-like peptide caused a developmental delay, which partially allowed the replacement of apoptotic cells. Thanks to a novel chronic ER stress model, these results establish a new pathway that both participates in tissue homeostasis and triggers apoptosis through an original regulation.