Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition.,Nature Chemical Biology

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Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition.
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2019-07-08 , DOI: 10.1038/s41589-019-0308-4
Clive Yik-Sham Chung _{1,

2} , Hijai R Shin _{3,

4} , Charles A Berdan ₅ , Breanna Ford ₅ , Carl C Ward _{2,

3} , James A Olzmann ₅ , Roberto Zoncu _{3,

4} , Daniel K Nomura _{1,

2,

3,

5}

Affiliation

Autophagy is a lysosomal degradation pathway that eliminates aggregated proteins and damaged organelles to maintain cellular homeostasis. A major route for activating autophagy involves inhibition of the mTORC1 kinase, but current mTORC1-targeting compounds do not allow complete and selective mTORC1 blockade. Here, we have coupled screening of a covalent ligand library with activity-based protein profiling to discover EN6, a small-molecule in vivo activator of autophagy that covalently targets cysteine 277 in the ATP6V1A subunit of the lysosomal v-ATPase, which activates mTORC1 via the Rag guanosine triphosphatases. EN6-mediated ATP6V1A modification decouples the v-ATPase from the Rags, leading to inhibition of mTORC1 signaling, increased lysosomal acidification and activation of autophagy. Consistently, EN6 clears TDP-43 aggregates, a causative agent in frontotemporal dementia, in a lysosome-dependent manner. Our results provide insight into how the v-ATPase regulates mTORC1, and reveal a unique approach for enhancing cellular clearance based on covalent inhibition of lysosomal mTORC1 signaling.

中文翻译：

共价靶向液泡 H+-ATP 酶可通过抑制 mTORC1 激活自噬。

自噬是一种溶酶体降解途径，可消除聚集的蛋白质和受损的细胞器以维持细胞稳态。激活自噬的主要途径涉及抑制 mTORC1 激酶，但目前的 mTORC1 靶向化合物不允许完全且选择性地阻断 mTORC1。在这里，我们将共价配体库的筛选与基于活性的蛋白质分析结合起来，发现 EN6，一种小分子体内自噬激活剂，共价靶向溶酶体 v-ATP 酶 ATP6V1A 亚基中的半胱氨酸 277，通过该酶激活 mTORC1拉格鸟苷三磷酸酶。EN6 介导的 ATP6V1A 修饰使 v-ATPase 与 Rags 解偶联，从而抑制 mTORC1 信号传导、增加溶酶体酸化和激活自噬。一致地，EN6 以溶酶体依赖性方式清除 TDP-43 聚集物，这是额颞叶痴呆的致病因子。我们的结果深入了解了 v-ATPase 如何调节 mTORC1，并揭示了一种基于溶酶体 mTORC1 信号共价抑制来增强细胞清除的独特方法。

更新日期：2019-07-09

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