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

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

doi:10.1186/ar3601

Abstract

In canonical NF-κB signaling pathway, a ubiquitin ligase called SCF (Skp1, Cul1, 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 poly-NEDD8 chain binding proteins (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.

Highlights

Acute isolated neurological syndromes, such as optic neuropathy or transverse myelopathy, may cause diagnostic problems since they can be the first presentations in a number of demyelinating disorders including multiple sclerosis (MS) and collagen diseases
tumor necrosis factor (TNF) therapy and demyelinating event: A report indicates that adverse events such as the demyelinating lesion in the brain, optic neuritis, and neuropathy occurred after treatment with anti-TNF alpha therapy in collagen disease, and TNF antagonizing therapy showed worsening in a clinical trial with MS
Believing on the similarities of normal joints in humans and monkeys, we have employed a model of collagen-induced arthritis in Macaca fascicularis in an attempt to evaluate the histological alterations caused by such condition in the extracellular matrix of the articular cartilage

Summary

Introduction

Acute isolated neurological syndromes, such as optic neuropathy or transverse myelopathy, may cause diagnostic problems since they can be the first presentations in a number of demyelinating disorders including multiple sclerosis (MS) and collagen diseases. Acute Serum Amyloid A (A-SAA) is an acute phase protein strongly expressed in rheumatoid arthritis (RA) synovial tissue (ST) critically involved in regulating cell migration and angiogenesis These processes are dependent on downstream interactions between extracellular matrix and cytoskeletal components. Conclusions: These results indicate that Egr-1 contributes to IL-1mediated down-regulation of PPARg expression in OA chondrocytes and suggest that this pathway could be a potential target for pharmacologic intervention in the treatment of OA and possibly other arthritic diseases. Immune cell-derived microparticles (MPs) are present at increased amounts in synovial fluid of rheumatoid arthritis (RA) patients [1] and can activate disease-relevant signalling pathways in RA synovial fibroblasts (SF) [2,3].

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