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

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

doi:10.1038/s41556-020-00583-9

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

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 HamasakiMasahiro Yamamoto, Yukinori Okada, Masaaki Komatsu, Takeharu Nagai, Yoshitsugu Takabatake, Haoxing Xu, Yoshitaka Isaka, Andrea Ballabio, Tamotsu Yoshimori

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149 Scopus citations

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.

Original language	English
Pages (from-to)	1252-1263
Number of pages	12
Journal	Nature Cell Biology
Volume	22
Issue number	10
DOIs	https://doi.org/10.1038/s41556-020-00583-9
State	Published - 1 Oct 2020
Externally published	Yes

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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., ... Yoshimori, T. (2020). LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury. Nature Cell Biology, 22(10), 1252-1263. https://doi.org/10.1038/s41556-020-00583-9

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title = "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.",

author = "Shuhei Nakamura and Saki Shigeyama and Satoshi Minami and Takayuki Shima and Shiori Akayama and Tomoki Matsuda and Alessandra Esposito and Gennaro Napolitano and Akiko Kuma and Tomoko Namba-Hamano and Jun Nakamura and Kenichi Yamamoto and Miwa Sasai and Ayaka Tokumura and Mika Miyamoto and Yukako Oe and Toshiharu Fujita and Seigo Terawaki and Atsushi Takahashi and Maho Hamasaki and Masahiro Yamamoto and Yukinori Okada and Masaaki Komatsu and Takeharu Nagai and Yoshitsugu Takabatake and Haoxing Xu and Yoshitaka Isaka and Andrea Ballabio and Tamotsu Yoshimori",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = oct,

day = "1",

doi = "10.1038/s41556-020-00583-9",

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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 2020, 'LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury', Nature Cell Biology, vol. 22, no. 10, pp. 1252-1263. https://doi.org/10.1038/s41556-020-00583-9

TY - JOUR

T1 - LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury

AU - Nakamura, Shuhei

AU - Shigeyama, Saki

AU - Minami, Satoshi

AU - Shima, Takayuki

AU - Akayama, Shiori

AU - Matsuda, Tomoki

AU - Esposito, Alessandra

AU - Napolitano, Gennaro

AU - Kuma, Akiko

AU - Namba-Hamano, Tomoko

AU - Nakamura, Jun

AU - Yamamoto, Kenichi

AU - Sasai, Miwa

AU - Tokumura, Ayaka

AU - Miyamoto, Mika

AU - Oe, Yukako

AU - Fujita, Toshiharu

AU - Terawaki, Seigo

AU - Takahashi, Atsushi

AU - Hamasaki, Maho

AU - Yamamoto, Masahiro

AU - Okada, Yukinori

AU - Komatsu, Masaaki

AU - Nagai, Takeharu

AU - Takabatake, Yoshitsugu

AU - Xu, Haoxing

AU - Isaka, Yoshitaka

AU - Ballabio, Andrea

AU - Yoshimori, Tamotsu

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41556-020-00583-9

DO - 10.1038/s41556-020-00583-9

M3 - Article

C2 - 32989250

AN - SCOPUS:85091610270

SN - 1465-7392

VL - 22

SP - 1252

EP - 1263

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 10

ER -

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

Abstract

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