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首页> 外文期刊>Cell death & disease. >Eiger-induced cell death relies on Rac1-dependent endocytosis
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Eiger-induced cell death relies on Rac1-dependent endocytosis

机译：艾格峰诱导的细胞死亡依赖于Rac1依赖性内吞作用

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Signaling via tumor necrosis factor receptor (TNFR) superfamily members regulates cellular life and death decisions. A subset of mammalian TNFR proteins, most notably the p75 neurotrophin receptor (p75NTR), induces cell death through a pathway that requires activation of c-Jun N-terminal kinases (JNKs). However the receptor-proximal signaling events that mediate this remain unclear. Drosophila express a single tumor necrosis factor (TNF) ligand termed Eiger (Egr) that activates JNK-dependent cell death. We have exploited this model to identify phylogenetically conserved signaling events that allow Egr to induce JNK activation and cell death in vivo . Here we report that Rac1, a small GTPase, is specifically required in Egr-mediated cell death. rac1 loss of function blocks Egr-induced cell death, whereas Rac1 overexpression enhances Egr-induced killing. We identify Vav as a GEF for Rac1 in this pathway and demonstrate that dLRRK functions as a negative regulator of Rac1 that normally acts to constrain Egr-induced death. Thus dLRRK loss of function increases Egr-induced cell death in the fly. We further show that Rac1-dependent entry of Egr into early endosomes is a crucial prerequisite for JNK activation and for cell death and show that this entry requires the activity of Rab21 and Rab7. These findings reveal novel regulatory mechanisms that allow Rac1 to contribute to Egr-induced JNK activation and cell death.
机译：通过肿瘤坏死因子受体（TNFR）超家族成员发出的信号调节细胞的生死决定。哺乳动物TNFR蛋白的一个子集，最著名的是p75神经营养蛋白受体（p75NTR），通过需要激活c-Jun N端激酶（JNK）的途径诱导细胞死亡。然而，尚不清楚介导此的受体近端信号事件。果蝇表达一种称为Eiger（Egr）的肿瘤坏死因子（TNF）配体，激活JNK依赖性细胞死亡。我们已经利用这个模型来识别进化上保守的信号事件，允许Egr在体内诱导JNK激活和细胞死亡。在这里，我们报告Rac1，小的GTPase，是Egr介导的细胞死亡中特别需要的。 rac1功能丧失会阻止Egr诱导的细胞死亡，而Rac1的过表达会增强Egr诱导的杀伤力。我们将Vav鉴定为该途径中Rac1的GEF，并证明dLRRK充当Rac1的负调节剂，Rac1通常起抑制Egr诱导的死亡的作用。因此，dLRRK功能丧失会增加果蝇引起的Egr诱导的细胞死亡。我们进一步表明，Rgr1依赖的Egr进入早期内体是JNK激活和细胞死亡的关键前提，并表明该进入需要Rab21和Rab7的活性。这些发现揭示了新的调节机制，使Rac1有助于Egr诱导的JNK激活和细胞死亡。

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