A dual function for deep orange in programmed autophagy in the Drosolphila melanogaster fat body
A dual function for deep orange in programmed autophagy in the Drosolphila melanogaster fat body
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DOI：
10.1016/j.yexcr.2006.03.002
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发表时间：
2006-07-01
影响因子：
3.7
通讯作者：
Stenmark, Harald
中科院分区：
文献类型：
--
作者：
Lindmo, Karine;Simonsen, Anne;Stenmark, Harald
通过自噬的溶酶体降解细胞质对于细胞氨基酸稳态和组织重塑至关重要。在果蝇等昆虫中，幼虫脂肪体在变态之前的自噬在发育上被上调。在此，自噬是由激素蜕皮激素通过下调自噬抑制性磷酸肌醇 3-激酶 (PI3K) 信号通路诱导的。在酵母中，Vps18 和 HOPS 复合体的其他成员被发现对于自噬降解至关重要。在果蝇中，Vps18 同源物深橙 (Dor) 先前已被证明可介导多囊泡内体与溶酶体的融合。还报道了 Dor 需要蜕皮激素介导的染色体膨胀。在本报告中，我们测试了这样的假设：Dor 可能在蜕皮激素信号水平上以及通过介导自噬体与溶酶体的融合来控制程序性自噬。我们发现dor突变体在程序化自噬方面存在缺陷，并提供了自噬在两个水平上被阻断的证据。首先，PI3K 活性在 dor 幼虫中没有正确下调，这与蜕皮激素报告基因活性的降低相关。通过给突变幼虫喂食蜕皮激素，PI3K 活性的下调得以恢复。其次，外源性蜕皮激素和 PTEN（PI3K 信号传导的沉默剂）的过度表达都无法恢复 dor 突变体脂肪体内自噬体与溶酶体的融合。这些结果表明，Dor 通过蜕皮激素信号传导间接控制自噬，也通过自溶酶体融合直接控制自噬。 (c) 2006 Elsevier Inc. 保留所有权利。
Lysosomal degradation of cytoplasm by way of autophagy is essential for cellular amino acid homeostasis and for tissue remodeling. In insects such as Drosophila, autophagy is developmentally upregulated in the larval fat body prior to metamorphosis. Here, autophagy is induced by the hormone ecdysone through down-regulation of the autophagy-suppressive phosphoinositide 3-kinase (PI3K) signaling pathway. In yeast, Vps18 and other members of the HOPS complex have been found essential for autophagic degradation. In Drosophila, the Vps18 homologue Deep orange (Dor) has previously been shown to mediate fusion of multivesicular endosomes with lysosomes. A requirement of Dor for ecdysone-mediated chromosome puffing has also been reported. In the present report, we have tested the hypothesis that Dor may control programmed autophagy at the level of ecdysone signaling as well as by mediating autophagosome-to-lysosome fusion. We show that dor mutants are defective in programmed autophagy and provide evidence that autophagy is blocked at two levels. First, PI3K activity was not down-regulated correctly in dor larvae, which correlated with a decrease in ecdysone reporter activity. The down-regulation of PI3K activity was restored by feeding ecdysone to the mutant larvae. Second, neither exogenous ecdysone nor overexpression of PTEN, a silencer of PI3K signaling, restored fusion of autophagosomes with lysosomes in the fat body of dor mutants. These results indicate that Dor controls autophagy indirectly, via ecdysone signaling, as well as directly, via autolysosomal fusion. (c) 2006 Elsevier Inc. All rights reserved.