Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential.
Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential.
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DOI：
10.1038/ncomms9620
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发表时间：
2015-10-27
影响因子：
16.6
通讯作者：
Deretic V
中科院分区：
文献类型：
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作者：
Chauhan S;Ahmed Z;Bradfute SB;Arko-Mensah J;Mandell MA;Won Choi S;Kimura T;Blanchet F;Waller A;Mudd MH;Jiang S;Sklar L;Timmins GS;Maphis N;Bhaskar K;Piguet V;Deretic V
自噬是一种保守的稳态过程，活跃在所有人类细胞中，并影响一系列疾病。在这里，我们使用药物筛选来发现自噬激活的新机制。我们确定了一个子集的药物诱导自噬通量的影响，在不同的细胞系统建模特定阶段的几种人类疾病，如艾滋病毒传播和过度磷酸化的tau蛋白积累在阿尔茨海默氏病。一种药物，氟苯达唑，是一种有效的诱导剂，通过影响乙酰化和动态微管以相互的方式启动和流动的自噬。氟苯达唑对动态微管的破坏导致mTOR失活和从溶酶体解离，导致TFEB（转录因子EB）核转位和自噬激活。通过诱导微管乙酰化，氟苯达唑激活JNK 1，导致Bcl-2磷酸化，导致Beclin 1从Bcl-2-Beclin 1复合物中释放，用于自噬诱导，从而揭示了一种新的诱导自噬通量的方法，该方法可能适用于疾病治疗。 自噬是一种体内平衡的过程，可能成为治疗疾病的潜在药物靶点。在这里，作者在药物筛选中确定氟苯达唑作为自噬起始和通量的诱导剂，通过影响微管、mTOR、TFEB和Beclin 1活性。
Autophagy is a conserved homeostatic process active in all human cells and affecting a spectrum of diseases. Here we use a pharmaceutical screen to discover new mechanisms for activation of autophagy. We identify a subset of pharmaceuticals inducing autophagic flux with effects in diverse cellular systems modelling specific stages of several human diseases such as HIV transmission and hyperphosphorylated tau accumulation in Alzheimer's disease. One drug, flubendazole, is a potent inducer of autophagy initiation and flux by affecting acetylated and dynamic microtubules in a reciprocal way. Disruption of dynamic microtubules by flubendazole results in mTOR deactivation and dissociation from lysosomes leading to TFEB (transcription factor EB) nuclear translocation and activation of autophagy. By inducing microtubule acetylation, flubendazole activates JNK1 leading to Bcl-2 phosphorylation, causing release of Beclin1 from Bcl-2-Beclin1 complexes for autophagy induction, thus uncovering a new approach to inducing autophagic flux that may be applicable in disease treatment. Autophagy is a homeostatic process that could be a potential drug target in the treatment of disease. Here the authors identify in a pharmaceutical screen flubendazole as an inducer of autophagy initiation and flux by affecting microtubules, mTOR, TFEB and Beclin 1 activity.