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This article is part of the supplement: Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Oral presentation

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

Osamu Takashima*, Fuminori Tsuruta, Manato Ebina, Yu Kigoshi, Shingo Nakamura and Tomoki Chiba

  • * Corresponding author: Osamu Takashima

Author Affiliations

Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305-8577, Japan

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Arthritis Research & Therapy 2012, 14(Suppl 1):O46  doi:10.1186/ar3601


The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/S1/O46


Published:9 February 2012

© 2012 Takashima et al.; licensee 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.

Oral presentation

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.

References

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    J Proteome Res 2008, 7:1274-1287. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  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. PubMed Abstract | Publisher Full Text OpenURL

  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. OpenURL