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論文
- タイトル
- タイトル（英）
- KEAP1 retention in phase-separated p62 bodies drives liver damage under autophagy-deficient conditions.
- 参照URL
- https://researchmap.jp/tsuchiya-hk/published_papers/50784971
- 著者
- 著者（英）
- Shuhei Takada,Nozomi Shinomiya,Gaoxin Mao,Hikaru Tsuchiya,Tomoaki Koga,Satoko Komatsu-Hirota,Yu-Shin Sou,Manabu Abe,Elena Ryzhii,Michitaka Suzuki,Mitsuyoshi Nakao,Satoshi Waguri,Hideaki Morishita,Masaaki Komatsu
- 担当区分
- 概要
- 概要（英）
- Phase-separated p62 bodies activate NRF2, a key transcription factor for antioxidant response, by sequestering KEAP1, which targets NRF2 for degradation. Although p62 bodies containing KEAP1 are degraded by autophagy, they accumulate in various liver disorders. Their precise disease role remains unclear. We show that excessive KEAP1 retention in p62 bodies and NRF2 activation are major causes of liver damage when autophagy is impaired. In mice with weakened or blocked p62-KEAP1 interactions, KEAP1 retention and NRF2 activation under autophagy-deficient conditions were suppressed. Transcriptome and proteome analyses reveal that p62 mutants unable to bind KEAP1 normalize the expression of NRF2 targets induced by defective autophagy. Autophagy deficiency causes organelle accumulation, especially of the ER, regardless of p62 mutation. Liver damage and hepatomegaly resulting from autophagy suppression markedly improved in mice carrying p62 mutants, particularly those with blocked KEAP1 binding. These findings highlight excessive KEAP1 retention in p62 bodies and defective organelle turnover as key drivers of liver pathology, underscoring the significance of phase separation in vivo.
- 出版者・発行元
- 出版者・発行元（英）
- 誌名
- 誌名（英）
- EMBO reports
- 巻
- 26
- 号
- 13
- 開始ページ
- 3384
- 終了ページ
- 3410
- 出版年月
- 2025年7月
- 査読の有無
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- DOI URL
- https://doi.org/10.1038/s44319-025-00483-9
- 共同研究・競争的資金等の研究課題
研究者
土屋 光
( )