Format

Send to

Choose Destination
Nat Chem Biol. 2019 Aug;15(8):776-785. doi: 10.1038/s41589-019-0308-4. Epub 2019 Jul 8.

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

Author information

1
Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
2
Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.
3
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
4
The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA, USA.
5
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA.
6
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. rzoncu@berkeley.edu.
7
The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA, USA. rzoncu@berkeley.edu.
8
Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. dnomura@berkeley.edu.
9
Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA. dnomura@berkeley.edu.
10
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. dnomura@berkeley.edu.
11
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA. dnomura@berkeley.edu.

Abstract

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.

PMID:
31285595
PMCID:
PMC6641988
[Available on 2020-01-08]
DOI:
10.1038/s41589-019-0308-4

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center