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- Publisher Website: 10.1038/s41589-019-0308-4
- Scopus: eid_2-s2.0-85068904434
- PMID: 31285595
- WOS: WOS:000476478500007
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Article: Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition
Title | Covalent targeting of the vacuolar H<sup>+</sup>-ATPase activates autophagy via mTORC1 inhibition |
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Authors | |
Issue Date | 2019 |
Citation | Nature Chemical Biology, 2019, v. 15, n. 8, p. 776-785 How to Cite? |
Abstract | © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. 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. |
Persistent Identifier | http://hdl.handle.net/10722/282681 |
ISSN | 2023 Impact Factor: 12.9 2023 SCImago Journal Rankings: 5.558 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Chung, Clive Yik Sham | - |
dc.contributor.author | Shin, Hijai R. | - |
dc.contributor.author | Berdan, Charles A. | - |
dc.contributor.author | Ford, Breanna | - |
dc.contributor.author | Ward, Carl C. | - |
dc.contributor.author | Olzmann, James A. | - |
dc.contributor.author | Zoncu, Roberto | - |
dc.contributor.author | Nomura, Daniel K. | - |
dc.date.accessioned | 2020-05-28T01:57:11Z | - |
dc.date.available | 2020-05-28T01:57:11Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Nature Chemical Biology, 2019, v. 15, n. 8, p. 776-785 | - |
dc.identifier.issn | 1552-4450 | - |
dc.identifier.uri | http://hdl.handle.net/10722/282681 | - |
dc.description.abstract | © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. 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. | - |
dc.language | eng | - |
dc.relation.ispartof | Nature Chemical Biology | - |
dc.title | Covalent targeting of the vacuolar H<sup>+</sup>-ATPase activates autophagy via mTORC1 inhibition | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1038/s41589-019-0308-4 | - |
dc.identifier.pmid | 31285595 | - |
dc.identifier.pmcid | PMC6641988 | - |
dc.identifier.scopus | eid_2-s2.0-85068904434 | - |
dc.identifier.volume | 15 | - |
dc.identifier.issue | 8 | - |
dc.identifier.spage | 776 | - |
dc.identifier.epage | 785 | - |
dc.identifier.eissn | 1552-4469 | - |
dc.identifier.isi | WOS:000476478500007 | - |
dc.identifier.issnl | 1552-4450 | - |