Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition

Chung, Clive Yik‐Sham; Shin, H; Berdan, Charles A.; Ford, Breanna; Ward, Carl C.; Olzmann, James A.; Zoncu, Roberto; Nomura, Daniel K.

doi:10.1038/s41589-019-0308-4

Cited by 128 publications

(102 citation statements)

References 62 publications

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“…, while siRNA-mediated knockdown induced autophagy activity in U87-MG cells67 , and KD of ATP6V1A in HeLa cells prevented drug-induced lysosomal acidification and autophagy activation50 . Under our experimental conditions, ATP6V1A CRISPRi in hiPSC neurons did not alter lysosomal acidification (data not shown) orimpact autophagy-related gene pathways.…”

mentioning

confidence: 88%

“…This gene encodes a component (V1 subunit A, V1a) of vacuolar ATPase (v-ATPase), a multi-subunit enzyme that mediates acidification of eukaryotic intracellular organelles. v-ATPase is a component of the mTOR pathway and functions as a lysosome-associated machinery for amino acid sensing 49,50 . A 15 potential role of ATP6V1A in neuronal development was suggested by studying de novo mutations in this gene 51 .…”

Section: Bayesian Network Analysis Predicts Novel Key Drivers Of Synamentioning

confidence: 99%

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Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Wang

Sekiya

et al. 2019

Preprint

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To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H + -ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

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confidence: 88%

Section: Bayesian Network Analysis Predicts Novel Key Drivers Of Synamentioning

confidence: 99%

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Wang

Sekiya

et al. 2019

Preprint

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“…This resulted in the discovery of lysosomal V‐ATPase catalytic subunit A protein as a new target protein of FK506. Very recently, EN6 was identified as a new bioactive small molecule to bind covalently with lysosomal V‐ATPase catalytic subunit A which is responsible for its autophagy‐enhancing activity, demonstrating that V‐ATPase catalytic subunit A could play a significant role in autophagy and verifying the binding of FK506 to V‐ATPase catalytic subunit A is responsible for its autophagy enhancing activity …”

Section: Target Selection With High Score Proteinsmentioning

confidence: 99%

Profiling the Protein Targets of Unmodified Bio‐Active Molecules with Drug Affinity Responsive Target Stability and Liquid Chromatography/Tandem Mass Spectrometry

et al. 2020

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Identifying the target proteins of bioactive small molecules is a key step in understanding mode-of-action of the drug and addressing the underlying mechanisms responsible for a particular phenotype. Proteomics has been successfully used to elucidate the target protein profiles of unmodified and ligand-modified bioactive small molecules. In the latter approach, compounds can be modified via click chemistry and combined with activity-based protein profiling. Target proteins are then enriched by performing a pull-down with the modified ligand. Methods that utilize unmodified bioactive small molecules include the cellular thermal shift assay, thermal proteome profiling, stability of proteins from rates of oxidation, and the drug affinity responsive target stability (DARTS) determination (or read-out). This review highlights recent proteomic approaches utilizing data-dependent analysis and data-independent analysis to identify target proteins by DARTS. When combined with liquid chromatography/tandem mass spectrometry, DARTS enables the identification of proteins that bind to drug molecules that leads to a conformational change in the target protein(s). In addition, an effective strategy is proposed for selecting the target protein(s) from within the pool of analyzed candidates. With additional complementary methods, the biologically relevant target proteins that bind to the small bio-active molecules can be further validated.

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“…The mutations associated with the severe phenotype result in loss of function and autophagy impairment (Fassio et al, 2018). On the contrary, covalent targeting of ATP6V1A has been recently shown to activate autophagy by increasing v-ATPase catalytic activity and inhibiting mTORC1 activation (Chung et al, 2019).…”

Section: Autophagy and Neurodevelopmental Disorder With Epilepsymentioning

confidence: 99%

Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy

Falace

Esposito

Aprile

et al. 2020

Front. Cell. Neurosci.

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Autophagy is a highly conserved degradative process that conveys dysfunctional proteins, lipids, and organelles to lysosomes for degradation. The post-mitotic nature, complex and highly polarized morphology, and high degree of specialization of neurons make an efficient autophagy essential for their homeostasis and survival. Dysfunctional autophagy occurs in aging and neurodegenerative diseases, and autophagy at synaptic sites seems to play a crucial role in neurodegeneration. Moreover, a role of autophagy is emerging for neural development, synaptogenesis, and the establishment of a correct connectivity. Thus, it is not surprising that defective autophagy has been demonstrated in a spectrum of neurodevelopmental disorders, often associated with early-onset epilepsy. Here, we discuss the multiple roles of autophagy in neurons and the recent experimental evidence linking neurodevelopmental disorders with epilepsy to genes coding for autophagic/lysosomal system-related proteins and envisage possible pathophysiological mechanisms ranging from synaptic dysfunction to neuronal death.

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Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition

Cited by 128 publications

References 62 publications

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Profiling the Protein Targets of Unmodified Bio‐Active Molecules with Drug Affinity Responsive Target Stability and Liquid Chromatography/Tandem Mass Spectrometry

Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy

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