Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage

Na Yeon Park, Doo Sin Jo, Jae-Yoon Yang, Ji-Eun Bae, Joon Bum Kim, Yong Hwan Kim, Seong Hyun Kim, Pansoo Kim, Dong-Seok Lee, Tamotsu Yoshimori, Eun-Kyeong Jo, Eunbyul Yeom () and Dong-Hyung Cho ()
Additional contact information
Na Yeon Park: Kyungpook National University
Doo Sin Jo: ORGASIS Corp. 260
Jae-Yoon Yang: Kyungpook National University
Ji-Eun Bae: Kyungpook National University
Joon Bum Kim: Kyungpook National University
Yong Hwan Kim: Kyungpook National University
Seong Hyun Kim: Kyungpook National University
Pansoo Kim: ORGASIS Corp. 260
Dong-Seok Lee: Kyungpook National University
Tamotsu Yoshimori: Osaka University
Eun-Kyeong Jo: Chungnam National University College of Medicine
Eunbyul Yeom: Kyungpook National University
Dong-Hyung Cho: Kyungpook National University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56294-y

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