PPAR gamma is an E3 ligase that induces the degradationof NF kappa B/p65

摘要

Nuclear factor-kappa B (NF kappa B) and peroxisome proliferator activated receptor-g (PPAR gamma) are bothtranscription factors that perform distinct but overlapping roles in cellular regulation. Here wereport that PPARg acts as an E3 ubiquitin ligase, physically interacting with p65 to induce itsubiquitination and degradation. The ligand-binding domain of PPARg interacts with the RelHomology Domain region of NF kappa B/p65 to undergo robust ubiquitination and degradationthat was independent of PPARg transcriptional activity. Moreover, the ligand-binding domainof PPARg delivered Lys48-linked polyubiquitin, resulting in the ubiquitination and degradationof p65. Lys28 was found to be critically important for PPARg-mediated ubiquitination anddegradation of p65, as it terminated both NFkB/p65-mediated pro-inflammatory responsesand xenograft tumours. These findings demonstrate that PPAR gamma E3 ubiquitin ligase activityinduces Lys48-linked ubiquitination and degradation of p65, and that this function is criticalto terminate NFkB signalling pathway-elicited inflammation and cancer.