Skp2 Attenuates Nf-Kappa B Signaling By Mediating Ikk Beta Degradation Through Autophagy

NF-kappa B signaling controls a large set of physiological processes ranging from inflammatory responses to cell death. Its activation is tightly regulated through controlling the activity and stability of multiple signaling components. Here, we identify that NF-kappa B activation is suppressed by an F-box protein, S-phase kinase associated protein 2 (SKP2). SKP2 deficiency enhanced NF-kappa B activation as well as the production of inflammatory cytokines. In addition, SKP2 potently blocked the NF-kappa B activation at the I kappa B kinase (IKK) level. Mechanistic study further revealed that SKP2 functions as an adaptor to promote an interaction between active IKK beta and the autophagic cargo receptor p62 to mediate IKK beta degradation via selective autophagy. These findings identify a previously unrecognized role of SKP2 in NF-kappa B activation by which SKP2 acts as a secondary receptor to assist IKK beta delivery to autophagosomes for degradation in a p62-dependent manner.