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LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury

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.

Authors

Shuhei Nakamura (1, 2, 3), Saki Shigeyama (1, 2), Satoshi Minami (4), Takayuki Shima (1, 2), Shiori Akayama (1, 2), Tomoki Matsuda (5), Alessandra Esposito (6), Gennaro Napolitano (6, 7), Akiko Kuma (1, 2), Tomoko Namba-Hamano (4), Jun Nakamura (4), Kenichi Yamamoto (8), Miwa Sasai (9, 10), Ayaka Tokumura (1, 2), Mika Miyamoto (1, 2), Yukako Oe (1, 2), Toshiharu Fujita (1, 2), Seigo Terawaki (11), Atsushi Takahashi (4), Maho Hamasaki (1, 2), Masahiro Yamamoto (9, 10), Yukinori Okada (8), Masaaki Komatsu (12), Takeharu Nagai (5), Yoshitsugu Takabatake (4), Haoxing Xu (13), Yoshitaka Isaka (4), Andrea Ballabio (6, 7, 14, 15, 16), Tamotsu Yoshimori (1, 2, 17)

  1. Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
  2. Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
  3. Institute for Advanced Co-Creation Studies, Osaka University, Osaka, Japan.
  4. Department of Nephrology, Graduate School of Medicine, Osaka University, Osaka, Japan.
  5. Department of Biomolecular Science and Engineering, The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.
  6. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  7. Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy.
  8. Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
  9. Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  10. Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
  11. Laboratory of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  12. Department of Physiology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
  13. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
  14. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  15. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
  16. SSM School for Advanced Studies, Federico II University, Naples, Italy.
  17. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan.
PubMed 32989250

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