Atg17/FIP200 localizes to perilysosomal Ref(2)P aggregates and promotes autophagy by activation of Atg1 in Drosophila.
Atg17/FIP200 localizes to perilysosomal Ref(2)P aggregates and promotes autophagy by activation of Atg1 in Drosophila.
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DOI：
10.4161/auto.27442
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发表时间：
2014-03
期刊：
影响因子：
13.3
通讯作者：
Juhász G
中科院分区：
文献类型：
--
作者：
Nagy P;Kárpáti M;Varga A;Pircs K;Venkei Z;Takáts S;Varga K;Erdi B;Hegedűs K;Juhász G
吞噬细胞衍生的自噬体将细胞质物质递送至溶酶体以进行降解和再利用。由不完全表征的Atg蛋白的作用介导的自噬涉及许多生理和病理环境，包括抗应激、免疫、衰老、癌症和神经退行性疾病。在这里，我们的特点是Atg 17/FIP 200，果蝇的直系同源哺乳动物RB 1CC 1/FIP 200，酵母Atg 17的功能等效物。atg 17中断抑制基础，饥饿诱导和发育自噬，并干扰变态过程中的幼虫唾液腺和中肠的程序化消除。饥饿后，Atg 17阳性结构出现在溶酶体附近的选择性货物Ref（2）P/p62的聚集体处。这个位置可能类似于酵母中描述的泡周PAS（噬菌体组装位点）。与哺乳动物一样，果蝇Atg 17也是Atg 1激酶复合物的成员，我们发现它与其他亚基结合，包括Atg 1、Atg 13和Atg 101（人类C12 orf 44、小鼠9430023 L20 Rik和大鼠RGD 1359310）。Atg 17是内源性Atg 1在体内的激酶活性所必需的，因为Atg 17的缺失阻止了内源性Atg 13向过度磷酸化形式的Atg 1依赖性转变，并且还阻断了饥饿期间点状Atg 1的定位。最后，我们发现，Atg 1过表达诱导自噬，并减少Atg 17无效突变体脂肪体细胞的细胞大小，并且Atg 17的过表达促进内源性Atg 13磷酸化，并增强自噬在Atg 1依赖的方式在脂肪体。我们提出了一个模型，根据该模型的相对活性的Atg 1，估计的比例hyper-to hypophosphorylated Atg 13，有助于设置低（基础）与高（饥饿诱导）的自噬水平在果蝇。
Phagophore-derived autophagosomes deliver cytoplasmic material to lysosomes for degradation and reuse. Autophagy mediated by the incompletely characterized actions of Atg proteins is involved in numerous physiological and pathological settings including stress resistance, immunity, aging, cancer, and neurodegenerative diseases. Here we characterized Atg17/FIP200, the Drosophila ortholog of mammalian RB1CC1/FIP200, a proposed functional equivalent of yeast Atg17. Atg17 disruption inhibits basal, starvation-induced and developmental autophagy, and interferes with the programmed elimination of larval salivary glands and midgut during metamorphosis. Upon starvation, Atg17-positive structures appear at aggregates of the selective cargo Ref(2)P/p62 near lysosomes. This location may be similar to the perivacuolar PAS (phagophore assembly site) described in yeast. Drosophila Atg17 is a member of the Atg1 kinase complex as in mammals, and we showed that it binds to the other subunits including Atg1, Atg13, and Atg101 (C12orf44 in humans, 9430023L20Rik in mice and RGD1359310 in rats). Atg17 is required for the kinase activity of endogenous Atg1 in vivo, as loss of Atg17 prevents the Atg1-dependent shift of endogenous Atg13 to hyperphosphorylated forms, and also blocks punctate Atg1 localization during starvation. Finally, we found that Atg1 overexpression induces autophagy and reduces cell size in Atg17-null mutant fat body cells, and that overexpression of Atg17 promotes endogenous Atg13 phosphorylation and enhances autophagy in an Atg1-dependent manner in the fat body. We propose a model according to which the relative activity of Atg1, estimated by the ratio of hyper- to hypophosphorylated Atg13, contributes to setting low (basal) vs. high (starvation-induced) autophagy levels in Drosophila.
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影响因子：
3.3
作者：
Jung, Chang Hwa;Jun, Chang Bong;Kim, Do-Hyung
通讯作者：
Kim, Do-Hyung
DOI：
10.1083/jcb.201009067
发表时间：
2011-01-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Itakura E;Mizushima N
通讯作者：
Mizushima N
影响因子：
4
作者：
Chen, Yongqiang;Klionsky, Daniel J.
通讯作者：
Klionsky, Daniel J.
影响因子：
3.3
作者：
Hosokawa, Nao;Hara, Taichi;Mizushima, Noboru
通讯作者：
Mizushima, Noboru
影响因子：
13.3
作者：
Itakura, Eisuke;Mizushima, Noboru
通讯作者：
Mizushima, Noboru