LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury
LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury
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DOI：
10.1038/s41556-020-00583-9
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发表时间：
2020-09-28
影响因子：
21.3
通讯作者：
Yoshimori, Tamotsu
中科院分区：
文献类型：
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作者：
Nakamura, Shuhei;Shigeyama, Saki;Yoshimori, Tamotsu
功能障碍的溶酶体的感知和清除对于细胞内稳态是至关重要的。在这里，我们表明，转录因子EB（TFEB）-一个主转录调节溶酶体的生物发生和自噬-在溶酶体损伤反应过程中被激活，其激活依赖于ATG共轭系统，介导LC 3脂化的功能。此外，溶酶体损伤触发溶酶体上的LC 3募集，其中脂化LC 3与溶酶体钙通道TRPML 1相互作用，促进TFEB活化所必需的钙流出。此外，我们证明了这种TFEB激活机制的存在和重要性，在肾脏中的草酸盐肾病伴溶酶体损伤的小鼠模型。近端小管特异性TFEB基因敲除小鼠表现出草酸盐晶体诱导的肾损伤进展。总之，我们的结果揭示了LC 3脂化激活TFEB的意外机制及其在溶酶体损伤反应期间的生理相关性。中村等人发现，溶酶体生物发生和自噬TFEB的主转录调节因子在溶酶体损伤期间的LC 3脂化之后被激活，并显示了该机制在肾损伤期间的重要性。
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.Nakamura et al. find that the master transcriptional regulator of lysosomal biogenesis and autophagy TFEB is activated following LC3 lipidation during lysosomal damage and show the importance of this mechanism during kidney injury.