RRC ID 68152
著者 Nakamura S, Shigeyama S, Minami S, Shima T, Akayama S, Matsuda T, Esposito A, Napolitano G, Kuma A, Namba-Hamano T, Nakamura J, Yamamoto K, Sasai M, Tokumura A, Miyamoto M, Oe Y, Fujita T, Terawaki S, Takahashi A, Hamasaki M, Yamamoto M, Okada Y, Komatsu M, Nagai T, Takabatake Y, Xu H, Isaka Y, Ballabio A, Yoshimori T.
タイトル LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury.
ジャーナル Nat Cell Biol
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.
巻・号 22(10)
ページ 1252-1263
公開日 2020-10-1
DOI 10.1038/s41556-020-00583-9
PII 10.1038/s41556-020-00583-9
PMID 32989250
MeSH Acute Kidney Injury / metabolism Acute Kidney Injury / pathology* Animals Autophagy* Autophagy-Related Protein 5 / genetics Autophagy-Related Protein 5 / metabolism Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism* Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology* Calcium / metabolism HeLa Cells Homeostasis Humans Lipids / chemistry* Lysosomes / metabolism Lysosomes / pathology* Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Microtubule-Associated Proteins / genetics Microtubule-Associated Proteins / metabolism*
IF 20.042
リソース情報
遺伝子材料 pcDNA3.1 3xFLAG::LC3A (RDB19195) pcDNA3.1 3xFLAG::LC3B (RDB19196) pcDNA3.1 3xFLAG::LC3B G120A (RDB19197) pcDNA3.1 3xFLAG::LC3C (RDB19198) pcDNA3.1 3xFLAG::GABARAP (RDB19199) pcDNA3.1 3xFLAG::GABARAPL1 (RDB19200) pcDNA3.1 3xFLAG::GABARAPL2 (RDB19201)