한빛사논문
- 조회3,017
Clive Yik-Sham Chung1,2,6, Hijai R. Shin3,4,6, Charles A. Berdan5, Breanna Ford5, Carl C. Ward2,3, James A. Olzmann5, Roberto Zoncu3,4* and Daniel K. Nomura1,2,3,5*
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 These authors contributed equally: Clive Yik-Sham Chung, Hijai R. Shin
*Correspondence to Roberto Zoncu or Daniel K. Nomura
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.
논문정보
- Research article
- 2019년 07월 (BRIC 등록일 2019-08-02)
- 국외 연구진
- 생명과학 > 분자생물학
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