LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury,Nature Cell Biology

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LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-09-28 , DOI: 10.1038/s41556-020-00583-9
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}

Affiliation

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

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.

中文翻译：

在肾损伤的溶酶体损伤反应过程中，LC3 脂化对于 TFEB 激活至关重要

感知和清除功能失调的溶酶体对于细胞稳态至关重要。在这里，我们显示转录因子 EB (TFEB) - 溶酶体生物发生和自噬的主要转录调节因子 - 在溶酶体损伤反应期间被激活，其激活取决于 ATG 结合系统的功能，该系统介导 LC3 脂化。此外，溶酶体损伤会触发溶酶体上的 LC3 募集，其中脂化的 LC3 与溶酶体钙通道 TRPML1 相互作用，促进对 TFEB 激活至关重要的钙流出。此外，我们在伴随溶酶体损伤的草酸盐肾病小鼠模型中证明了这种 TFEB 激活机制在肾脏中的存在和重要性。近端小管特异性 TFEB 敲除小鼠表现出草酸盐晶体诱导的肾损伤进展。

更新日期：2020-09-28

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