Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway.
Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway.
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DOI：
10.1083/jcb.200510065
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发表时间：
2006-02-27
影响因子：
7.8
通讯作者：
Rothman, James E
中科院分区：
文献类型：
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作者：
Yamamoto, Ai;Cremona, M Laura;Rothman, James E
多聚谷氨酰胺疾病如亨廷顿氏病（HD）的条件小鼠模型已经揭示，如果突变转基因的连续产生停止，细胞可以清除积累的致病蛋白。因此，蛋白质的清除导致小鼠疾病症状的消退。鉴于这些发现，确定负责减轻这种蛋白质积累的途径以确定对抗这些疾病的靶点至关重要。在HD的功能性遗传筛选中，我们发现胰岛素受体底物-2的活化，其介导胰岛素和胰岛素样生长因子1的信号级联，导致累积蛋白的大自噬介导的清除。尽管激活了Akt、哺乳动物雷帕霉素靶蛋白（mTOR）和S6激酶，但仍触发了巨自噬，但仍需要先前参与巨自噬的蛋白质，如Beclin 1和hVps 34。这些发现表明突变蛋白的积累可导致mTOR非依赖性的大自噬，并且溶酶体介导的积累蛋白的降解不同于饥饿条件下的降解。
Conditional mouse models of polyglutamine diseases, such as Huntington's disease (HD), have revealed that cells can clear accumulated pathogenic proteins if the continuous production of the mutant transgene is halted. Invariably, the clearance of the protein leads to regression of the disease symptoms in mice. In light of these findings, it is critical to determine the pathway responsible for alleviating this protein accumulation to define targets to fight these diseases. In a functional genetic screen of HD, we found that activation of insulin receptor substrate-2, which mediates the signaling cascades of insulin and insulin-like growth factor 1, leads to a macroautophagy-mediated clearance of the accumulated proteins. The macroautophagy is triggered despite activation of Akt, mammalian target of rapamycin (mTOR), and S6 kinase, but still requires proteins previously implicated in macroautophagy, such as Beclin1 and hVps34. These findings indicate that the accumulation of mutant protein can lead to mTOR-independent macroautophagy and that lysosome-mediated degradation of accumulated protein differs from degradation under conditions of starvation.