Takada Shuhei, Shinomiya Nozomi, Mao Gaoxin, Tsuchiya Hikaru, Koga Tomoaki, Komatsu-Hirota Satoko, Sou Yu-Shin, Abe Manabu, Ryzhii Elena, Suzuki Michitaka, Nakao Mitsuyoshi, Waguri Satoshi, Morishita Hideaki, Komatsu Masaaki
Department of Physiology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
Autophagy Research Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
EMBO Rep. 2025 May 28. doi: 10.1038/s44319-025-00483-9.
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.
相分离的p62小体通过隔离KEAP1来激活NRF2（一种抗氧化反应的关键转录因子），KEAP1会靶向NRF2使其降解。虽然含有KEAP1的p62小体可通过自噬降解，但它们在各种肝脏疾病中会积累。其确切的疾病作用仍不清楚。我们发现，当自噬受损时，KEAP1在p62小体中的过度滞留和NRF2激活是肝损伤的主要原因。在p62-KEAP1相互作用减弱或受阻的小鼠中，自噬缺陷条件下KEAP1的滞留和NRF2的激活受到抑制。转录组和蛋白质组分析表明，无法结合KEAP1的p62突变体可使由自噬缺陷诱导的NRF2靶标的表达正常化。无论p62是否发生突变，自噬缺陷都会导致细胞器积累，尤其是内质网。携带p62突变体的小鼠，尤其是那些KEAP1结合受阻的小鼠，自噬抑制引起的肝损伤和肝肿大明显改善。这些发现突出了KEAP1在p62小体中的过度滞留和细胞器周转缺陷是肝脏病理的关键驱动因素，强调了体内相分离的重要性。
