TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation

Neddylation is a process similar to ubiquitination, and is critical in various inflammatory diseases; however, its importance in the pathogenesis of inflammatory arthritis is not well understood. Here, we investigated the role of neddylation in collagen-induced arthritis (CIA) and its clinical relev...

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Bibliographic Details
Published in:Laboratory investigation 2019-04, Vol.99 (4), p.528-538
Main Authors: Liu, Kewei, Chen, Kaizhe, Zhang, Qian, Zhang, Lianfang, Yan, Yufei, Guo, Changjun, Qi, Jin, Yang, Kai, Wang, Fei, Huang, Ping, Guo, Lei, Deng, Lianfu, Li, Changwei
Format: Article
Language:English
Subjects:
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Activation
Animals
Arthritis
Arthritis - metabolism
Cell proliferation
Cells, Cultured
Collagen
Conjugation
Cullin
Fibroblasts
HEK293 Cells
Humans
Inflammatory diseases
Inflammatory response
Laboratory Medicine
Male
Medicine
Medicine & Public Health
Mice
NEDD8 Protein - metabolism
NF-kappa B - metabolism
NF-κB protein
Pathogenesis
Pathology
Post-transcription
Protein Processing, Post-Translational - physiology
Synovitis
TNF Receptor-Associated Factor 6 - metabolism
TRAF6 protein
Tumor necrosis factor
Tumor necrosis factor receptors
Ubiquitination
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Summary:Neddylation is a process similar to ubiquitination, and is critical in various inflammatory diseases; however, its importance in the pathogenesis of inflammatory arthritis is not well understood. Here, we investigated the role of neddylation in collagen-induced arthritis (CIA) and its clinical relevance. We showed that neddylation-related genes, including NEDD8 and CULLIN-1, were significantly upregulated in inflamed arthritic synovia. Functionally, neddylation activation was crucial for synovitis of CIA, as the inhibition of neddylation by MLN4924 significantly suppressed synovial cell proliferation and inflammatory responses. Mechanistically, neddylation mediated inflammatory arthritis by regulating NF-κB activation in fibroblast-like synovial cells (FLSs). Furthermore, TNF receptor-associated factor 6 (TRAF6) neddylation at Lys124 was essential for IL-17A-induced NF-κB activation. Replacing the Lys-124 residue with Arg (K124R) resulted in significantly impaired conjugation of NEDD8 to TRAF6, as well as markedly attenuated IL-17A-induced NF-κB activity. Therefore, the pathogenic role of neddylation in CIA as well as its mechanism of action demonstrated here provides a new insight into understanding the role of post-transcriptional modifications in the arthritis inflammatory response.
ISSN:0023-6837
1530-0307
DOI:10.1038/s41374-018-0175-8