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A novel NEDD8-binding protein modulates NF-κB signaling pathway
Arthritis Research & Therapyvolume 14, Article number: O46 (2012)
In canonical NF-κB signaling pathway, a ubiquitin ligase called SCF (S kp1, C ul1, F-box protein) complex is essential for I-κB degradation. The activity of the SCF complex is positively regulated by a post-translational modification of Cul1 subunit with a ubiquitin-like protein NEDD8. Like ubiquitin, NEDD8 possesses evolutionary conserved Lys residues on its surface, and forms poly-NEDD8 chain in vivo and in vitro [1, 2]. Despite the importance of the NEDD8 modification in all eukaryotic cells, little is known about the function of poly-NEDD8 chain. To elucidate the function of the poly-NEDD8 chain in vivo, we screened p oly-N EDD8 chain b inding p roteins (PNBPs) using a yeast two-hybrid system. Of the identified PNBPs, PNBP1 was identical to a gene present in non-HLA celiac disease and rheumatoid arthritis risk loci .
PNBP1 interacted with NEDD8, NEDD8-conjugating enzyme Ubc12 and Cul1. PNBP1 strongly associated with wild-type Cul1, but not its NEDDylation defective Cul1(K720R) mutant, suggesting that the interaction is mediated in part through NEDD8. Furthermore, PNBP1 promoted NEDDylation of Cul1 in an in vitro reconstitution assay. These activities were dependent on RING-finger domain of PNBP1. Finally, knockdown of PNBP1 led to reduction of the NF-κB activation, suggesting that PNBP1 is an important modulator of the NF-κB signaling pathway.
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