| Literature DB >> 32989250 |
Shuhei Nakamura1,2,3, Saki Shigeyama4,5, Satoshi Minami6, Takayuki Shima4,5, Shiori Akayama4,5, Tomoki Matsuda7, Alessandra Esposito8, Gennaro Napolitano8,9, Akiko Kuma4,5, Tomoko Namba-Hamano6, Jun Nakamura6, Kenichi Yamamoto10, Miwa Sasai11,12, Ayaka Tokumura4,5, Mika Miyamoto4,5, Yukako Oe4,5, Toshiharu Fujita4,5, Seigo Terawaki13, Atsushi Takahashi6, Maho Hamasaki4,5, Masahiro Yamamoto11,12, Yukinori Okada10, Masaaki Komatsu14, Takeharu Nagai7, Yoshitsugu Takabatake6, Haoxing Xu15, Yoshitaka Isaka6, Andrea Ballabio8,9,16,17,18, Tamotsu Yoshimori19,20,21.
Abstract
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.Entities:
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Year: 2020 PMID： 32989250 DOI： 10.1038/s41556-020-00583-9
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.213