Lithium induces autophagy by inhibiting inositol monophosphatase.
Lithium induces autophagy by inhibiting inositol monophosphatase.
复制标题
锂通过抑制肌醇单磷酸酶诱导自噬。
DOI：
10.1083/jcb.200504035
复制
发表时间：
2005-09-26
影响因子：
7.8
通讯作者：
Rubinsztein, David C
中科院分区：
文献类型：
--
作者：
Sarkar, Sovan;Floto, R Andres;Berger, Zdenek;Imarisio, Sara;Cordenier, Axelle;Pasco, Matthieu;Cook, Lynnette J;Rubinsztein, David C
大自噬是清除易聚集的胞质蛋白的关键途径。目前，上调哺乳动物细胞自噬的唯一合适的药理学策略是使用雷帕霉素，它抑制哺乳动物雷帕霉素靶蛋白（mTOR），这是自噬的负调节因子。在这里，我们描述了一种新的mTOR独立的途径，调节自噬。我们发现，锂诱导自噬，从而增强自噬底物的清除，如突变亨廷顿蛋白和α-突触核蛋白。这种作用不是由糖原合成酶激酶3β抑制介导的。锂的自噬增强特性是通过抑制肌醇单磷酸酶介导的，并导致游离肌醇耗尽。这反过来又降低了肌醇-1，4，5-三磷酸（IP 3）水平。我们的数据表明，自噬作用是在降低的IP 3水平（或下游）介导的，因为它被增加IP 3的药物治疗所消除。这种用于自噬诱导的新的药理学策略不依赖于mTOR，并且可能有助于治疗神经退行性疾病，如亨廷顿病，其中毒性蛋白是自噬底物。
Macroautophagy is a key pathway for the clearance of aggregate-prone cytosolic proteins. Currently, the only suitable pharmacologic strategy for up-regulating autophagy in mammalian cells is to use rapamycin, which inhibits the mammalian target of rapamycin (mTOR), a negative regulator of autophagy. Here we describe a novel mTOR-independent pathway that regulates autophagy. We show that lithium induces autophagy, and thereby, enhances the clearance of autophagy substrates, like mutant huntingtin and α-synucleins. This effect is not mediated by glycogen synthase kinase 3β inhibition. The autophagy-enhancing properties of lithium were mediated by inhibition of inositol monophosphatase and led to free inositol depletion. This, in turn, decreased myo-inositol-1,4,5-triphosphate (IP3) levels. Our data suggest that the autophagy effect is mediated at the level of (or downstream of) lowered IP3, because it was abrogated by pharmacologic treatments that increased IP3. This novel pharmacologic strategy for autophagy induction is independent of mTOR, and may help treatment of neurodegenerative diseases, like Huntington's disease, where the toxic protein is an autophagy substrate.