Volume 14 Supplement 1

Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Open Access

A novel NEDD8-binding protein modulates NF-κB signaling pathway

  • Osamu Takashima1,
  • Fuminori Tsuruta1,
  • Manato Ebina1,
  • Yu Kigoshi1,
  • Shingo Nakamura1 and
  • Tomoki Chiba1
Arthritis Research & Therapy201214(Suppl 1):O46

DOI: 10.1186/ar3601

Published: 29 February 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 [3].

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.

Authors’ Affiliations

Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennodai


  1. Jones J, Wu K, Yang Y, Guerrero C, Nillegoda N, Pan ZQ, Huang L: A targeted proteomic analysis of the ubiquitin-like modifier NEDDD8 and associated proteins. J Proteome Res. 2008, 7: 1274-1287. 10.1021/pr700749v.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Ohki Y, Funatsu N, Konishi N, Chiba T: The mechanism of poly-NEDD8 chain formation in vitro. Biochem Biophys Res Commun. 2009, 381: 443-447. 10.1016/j.bbrc.2009.02.090.View ArticlePubMedGoogle Scholar
  3. Alexandra Zhernakova A, et al: Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PloS Genet. 2011, 7: e10020004-Google Scholar


© Takashima et al.; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.