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Iso-seco-tanapartholide induces p62 covalent oligomerization to activate KEAP1-NRF2 redox pathway in rheumatoid
Dongrong Zhu1, Min Kong2, Chen Chen2
1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China; School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin, China.
Abstract:
SQSTM1/p62 sequesters intracellular aberrant proteins and mediates their selective autophagic degradation. p62 oligomerization posttranslational modification enhances its sequestration function and positively regulates the KEAP1-NRF2 redox pathway. However, the regulation of p62 covalent oligomerization has yet been poorly characterized. Here, we identified a natural small-molecule sesquiterpene, Iso-seco-tanapartholide (IST) modified p62 cysteine residues, which induced p62 to form crosslinked oligomers between TBS and TBS or TBS and PB1 domains in a covalently non-disulfide-linked manner. Using LC-MS/MS analysis and complementary approaches, we revealed that Cys residues of p62 were necessary for IST-induced covalent oligomer. This oligomerization promoted p62 recruitment of KEAP1 for degradation by autophagosomes and released NRF2 to the nucleus to activate the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. Accordingly, IST-mediated p62/NRF2 activation conferred protection from oxidative and inflammatory destruction of rheumatoid arthritis in vitro and in vivo. In contrast, p62-knockdown cells displayed a reduced anti-oxidant response and increased pro-inflammatory cytokine secretion in response to TNF-α stimulation. Hence, our findings uncover an unrecognized role of IST in the regulation of p62 oligomerization and provide a new strategy for the treatment of rheumatoid arthritis.
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