Journal
NATURE CELL BIOLOGY
Volume 22, Issue 10, Pages 1252-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41556-020-00583-9
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Funding
- AMED-PRIME [17gm6110003h0001]
- JSPS KAKENHI [17H05064]
- Senri Life Science Foundation
- Takeda Science Foundation
- Nakajima Foundation
- MSD Life Science Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- JST CREST [JPMJCR17H6]
- AMED [JP19gm5010001]
- JSPS A3 Foresight Program
- HFSP research grant
- Italian Telethon Foundation [TGM16CB6]
- MIUR FIRB [RBAP11Z3YA]
- European Research Council [694282]
- Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.)
- US National Institutes of Health [R01-NS078072]
- Huffington foundation
- European Regional Development Fund-POR Campania FESR 2014/2020
- MIUR PRIN [2017YF9FBS]
- University of Naples 'Federico II' STAR L1 2018
- Associazione Italiana per la Ricerca sul Cancro MFAG 2019 [23538]
- European Research Council (ERC) [694282] Funding Source: European Research Council (ERC)
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Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)-a master transcriptional regulator of lysosomal biogenesis and autophagy-is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response. Nakamura et al. find that the master transcriptional regulator of lysosomal biogenesis and autophagy TFEB is activated following LC3 lipidation during lysosomal damage and show the importance of this mechanism during kidney injury.
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