Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage
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 compl...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56294-y |
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| author | 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 Dong-Hyung Cho |
| author_facet | 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 Dong-Hyung Cho |
| author_sort | Na Yeon Park |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ee488fa693ea45bab3a06ec32202ce1d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ee488fa693ea45bab3a06ec32202ce1d2025-02-02T12:32:19ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-025-56294-yActivation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damageNa Yeon Park0Doo Sin Jo1Jae-Yoon Yang2Ji-Eun Bae3Joon Bum Kim4Yong Hwan Kim5Seong Hyun Kim6Pansoo Kim7Dong-Seok Lee8Tamotsu Yoshimori9Eun-Kyeong Jo10Eunbyul Yeom11Dong-Hyung Cho12School of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National UniversityORGASIS Corp. 260School of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National UniversityOrganelle Institute, Kyungpook National UniversitySchool of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National UniversitySchool of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National UniversitySchool of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National UniversityORGASIS Corp. 260School of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National UniversityDepartment of Genetics, Graduate School of Medicine, Osaka UniversityDepartment of Microbiology, Chungnam National University College of MedicineSchool of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National UniversitySchool of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National UniversityAbstract 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.https://doi.org/10.1038/s41467-025-56294-y |
| spellingShingle | 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 Dong-Hyung Cho Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage Nature Communications |
| title | Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage |
| title_full | Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage |
| title_fullStr | Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage |
| title_full_unstemmed | Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage |
| title_short | Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage |
| title_sort | activation of lysophagy by a tbk1 scffbxo3 tmem192 tax1bp1 axis in response to lysosomal damage |
| url | https://doi.org/10.1038/s41467-025-56294-y |
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