Iso-seco-tanapartholide induces p62 covalent oligomerization to activate KEAP1-NRF2 redox pathway in rheumatoid arthritis

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.

Iso-seco-tanapartholide; Keap1-NRF2; P62 oligomerization; Rheumatoid arthritis.