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自噬相关基因（ATG）偶联依赖/非依赖机制是溶酶体应激诱导的转录因子EB（TFEB）调控的基础。

ATG conjugation-dependent/independent mechanisms underlie lysosomal stress-induced TFEB regulation.

作者信息

Akayama Shiori, Shima Takayuki, Kaminishi Tatsuya, Cui Mengying, Monfregola Jlenia, Nishino Kohei, Ballabio Andrea, Kosako Hidetaka, Yoshimori Tamotsu, Nakamura Shuhei

机构信息

Graduate School of Frontier Biosciences, Osaka University , Suita, Japan.

Department of Biochemistry, Nara Medical University, Kashihara, Japan.

出版信息

J Cell Biol. 2025 Oct 6;224(10). doi: 10.1083/jcb.202307079. Epub 2025 Aug 29.

DOI:10.1083/jcb.202307079
PMID:40880129
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12396377/
Abstract

TFEB, a master regulator of autophagy and lysosomal biogenesis, is activated by several cellular stresses including lysosomal damage, but its underlying mechanism is unclear. TFEB activation during lysosomal damage depends on the ATG conjugation system, which mediates lipidation of ATG8 proteins. Here, we newly identify ATG conjugation-independent TFEB regulation that precedes ATG conjugation-dependent regulation, designated Modes I and II, respectively. We reveal unique regulators of TFEB in each mode: APEX1 in Mode I and CCT7 and/or TRIP6 in Mode II. APEX1 interacts with TFEB independently of the ATG conjugation system, and is required for TFEB stability, while both CCT7 and TRIP6 accumulate on lysosomes during lysosomal damage, and interact with TFEB mainly in ATG conjugation system-deficient cells, presumably blocking TFEB activation. TFEB activation by several other stresses also involves either Mode I or Mode II. Our results pave the way for a unified understanding of TFEB regulatory mechanisms from the perspective of the ATG conjugation system under a variety of cellular stresses.

摘要

转录因子EB（TFEB）是自噬和溶酶体生物合成的主要调节因子，可被包括溶酶体损伤在内的多种细胞应激激活，但其潜在机制尚不清楚。溶酶体损伤期间的TFEB激活依赖于ATG缀合系统，该系统介导ATG8蛋白的脂化。在这里，我们新发现了不依赖于ATG缀合的TFEB调节，它先于依赖于ATG缀合的调节，分别命名为模式I和模式II。我们揭示了每种模式下TFEB的独特调节因子：模式I中的APEX1以及模式II中的CCT7和/或TRIP6。APEX1独立于ATG缀合系统与TFEB相互作用，是TFEB稳定性所必需的，而在溶酶体损伤期间，CCT7和TRIP6都在溶酶体上积累，并且主要在缺乏ATG缀合系统的细胞中与TFEB相互作用，可能会阻断TFEB的激活。其他几种应激对TFEB的激活也涉及模式I或模式II。我们的结果为从ATG缀合系统的角度统一理解各种细胞应激下的TFEB调节机制铺平了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/481f3dbe2895/jcb_202307079_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/f505e735bc49/jcb_202307079_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/987166d8b891/jcb_202307079_figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/5ac719992dec/jcb_202307079_figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/b815c7a8ed9e/jcb_202307079_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/0ff3a1053a23/jcb_202307079_figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/387db3ff4bc5/jcb_202307079_figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/a3baf553ae98/jcb_202307079_figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/c9e4a4cb1607/jcb_202307079_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/6fc37002a986/jcb_202307079_figs6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/aa59af67a8e1/jcb_202307079_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/3c30461c29cd/jcb_202307079_figs7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/481f3dbe2895/jcb_202307079_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/f505e735bc49/jcb_202307079_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/987166d8b891/jcb_202307079_figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/5ac719992dec/jcb_202307079_figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/b815c7a8ed9e/jcb_202307079_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/0ff3a1053a23/jcb_202307079_figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/387db3ff4bc5/jcb_202307079_figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/a3baf553ae98/jcb_202307079_figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/c9e4a4cb1607/jcb_202307079_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/6fc37002a986/jcb_202307079_figs6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/aa59af67a8e1/jcb_202307079_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/3c30461c29cd/jcb_202307079_figs7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/87ad/12396377/481f3dbe2895/jcb_202307079_fig5.jpg

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本文引用的文献

[1]
Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.

Science. 2023-4-21

[2]
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EMBO J. 2022-12-15

[3]
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Nature. 2022-9

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Trends Cell Biol. 2022-11

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Sci Adv. 2021-10

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