フジタ　トシハル   Toshiharu Fujita   藤田　敏治    所属   川崎医科大学  医学部 基礎医学　分子遺伝医学    職種   助教
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury.
掲載誌名	正式名：Nature cell biology 略　 称：Nat Cell Biol ISSNコード：14764679/14657392
掲載区分	国外
巻・号・頁	22(10),pp.1252-1263
著者・共著者	Shuhei Nakamura, Saki Shigeyama, Satoshi Minami, Takayuki Shima, Shiori Akayama, Tomoki Matsuda, Alessandra Esposito, Gennaro Napolitano, Akiko Kuma, Tomoko Namba-Hamano, Jun Nakamura, Kenichi Yamamoto, Miwa Sasai, Ayaka Tokumura, Mika Miyamoto, Yukako Oe, Toshiharu Fujita, Seigo Terawaki, Atsushi Takahashi, Maho Hamasaki, Masahiro Yamamoto, Yukinori Okada, Masaaki Komatsu, Takeharu Nagai, Yoshitsugu Takabatake, Haoxing Xu, Yoshitaka Isaka, Andrea Ballabio, Tamotsu Yoshimori
発行年月	2020/10
概要	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.
DOI	10.1038/s41556-020-00583-9
PMID	32989250