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Nat. Commun., 28 January 2025 | https://doi.org/10.1038/s41467-025-56294-y
Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage
Na Yeon Park1,2, Doo Sin Jo3, Jae-Yoon Yang1, Ji-Eun Bae2,4, Joon Bum Kim1, Yong Hwan Kim1, Seong Hyun Kim1, Pansoo Kim3, Dong-Seok Lee1, Tamotsu Yoshimori5, Eun-Kyeong Jo6, Eunbyul Yeom1,4 & Dong-Hyung Cho1,2,3
1School of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National University, Daegu, South Korea.
2Organelle Institute, Kyungpook National University, Daegu, South Korea.
3ORGASIS Corp. 260, Suwon, South Korea.
4KNU G-LAMP Project Group, KNU Institute of Basic Sciences, College of Natural Sciences, Kyungpook National University, Daegu, South Korea.
5Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
6Department of Microbiology, Chungnam National University College of Medicine, Daejeon, South Korea.
Corresponding authors
Correspondence to Eunbyul Yeom or Dong-Hyung Cho.
1School of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National University, Daegu, South Korea.
2Organelle Institute, Kyungpook National University, Daegu, South Korea.
3ORGASIS Corp. 260, Suwon, South Korea.
4KNU G-LAMP Project Group, KNU Institute of Basic Sciences, College of Natural Sciences, Kyungpook National University, Daegu, South Korea.
5Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
6Department of Microbiology, Chungnam National University College of Medicine, Daejeon, South Korea.
Corresponding authors
Correspondence to Eunbyul Yeom or Dong-Hyung Cho.
Abstract
Lysophagy eliminates damaged lysosomes and is crucial to cellular homeostasis; however, its underlying mechanisms are not entirely understood. We screen a ubiquitination-related compound library and determine that the substrate recognition component of the SCF-type E3 ubiquitin ligase complex, SCFFBXO3(FBXO3), which is a critical lysophagy regulator. Inhibition of FBXO3 reduces lysophagy and lysophagic flux in response to L-leucyl-L-leucine methyl ester (LLOMe). Furthermore, FBXO3 interacts with TMEM192, leading to its ubiquitination in LLOMe-treated cells. We also identify TAX1BP1 as a critical autophagic adaptor that recognizes ubiquitinated TMEM192 during lysophagy and find that TBK1 activation is crucial for lysophagy, as it phosphorylates FBXO3 in response to lysosomal damage. Knockout of FBXO3 significantly impairs lysophagy, and its reconstitution with a loss-of-function mutant (V221I) further confirms its essential role in lysophagy regulation. Collectively, our findings highlight the significance of the TBK1-FBXO3-TMEM192-TAX1BP1 axis in lysophagy and emphasize the critical role of FBXO3 in lysosomal integrity.
논문정보
- Research article
- 2025년 01월 (BRIC 등록일 2025-02-01)
- 국내(교신)+국외 연구진
- 생명과학 > 세포생물학
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