Nature Chemical Biology, 2019
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Monday, July 8, 2019
Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition [@RobertoZoncu @DanNomura @OlzmannLab @Clive_chung @HijaiShin]
Clive Yik-Sham Chung, Hijai R. Shin, Charles A. Berdan, Breanna Ford, Carl C. Ward, James A. Olzmann, Roberto Zoncu & Daniel K. Nomura
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.
Lysine-Targeted Covalent Inhibitors of PI3Kδ Synthesis and Screening by In Situ Interaction Upgradation
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