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药物筛选确定了具有广泛转化潜力的自噬激活新靶点过程。

Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential.

作者信息

Chauhan Santosh, Ahmed Zahra, Bradfute Steven B, Arko-Mensah John, Mandell Michael A, Won Choi Seong, Kimura Tomonori, Blanchet Fabien, Waller Anna, Mudd Michal H, Jiang Shanya, Sklar Larry, Timmins Graham S, Maphis Nicole, Bhaskar Kiran, Piguet Vincent, Deretic Vojo

机构信息

Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.

Cardiff Institute of Infection &Immunity, Cardiff University, School of Medicine, Henry Wellcome Building, Heath Park CF14 4XN, Cardiff, UK.

出版信息

Nat Commun. 2015 Oct 27;6:8620. doi: 10.1038/ncomms9620.

DOI:10.1038/ncomms9620
PMID:26503418
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4624223/
Abstract

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.

摘要

自噬是一种在所有人类细胞中都活跃的保守性稳态过程，且与一系列疾病相关。在此，我们通过药物筛选来发现激活自噬的新机制。我们鉴定出了一类能诱导自噬通量的药物，它们在模拟多种人类疾病特定阶段的不同细胞系统中发挥作用，比如HIV传播以及阿尔茨海默病中过度磷酸化tau蛋白的积累。一种药物，氟苯达唑，通过以一种相互作用的方式影响乙酰化和动态微管，成为自噬起始和通量的有效诱导剂。氟苯达唑对动态微管的破坏导致mTOR失活并从溶酶体解离，进而导致转录因子EB（TFEB）核转位并激活自噬。通过诱导微管乙酰化，氟苯达唑激活JNK1，导致Bcl-2磷酸化，促使Beclin1从Bcl-2-Beclin1复合物中释放出来以诱导自噬，从而揭示了一种可能适用于疾病治疗的诱导自噬通量的新方法。

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Autophagy. 2024 Aug;20(8):1879-1894. doi: 10.1080/15548627.2024.2334111. Epub 2024 Mar 27.
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