2. Academic Validation
  3. TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation

TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation

  • Lab Invest. 2019 Apr;99(4):528-538. doi: 10.1038/s41374-018-0175-8.
Kewei Liu 1,  Kaizhe Chen 1,  Qian Zhang 2,  Lianfang Zhang 3,  Yufei Yan 1,  Changjun Guo 1,  Jin Qi 1,  Kai Yang 1,  Fei Wang 1,  Ping Huang 1,  Lei Guo 4,  Lianfu Deng 5,  Changwei Li 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China.
  • 2 Department of Orthopedic Surgery, Guanghua Integrative Medicine Hospital, No.540 Xinhua Road, 200052, Shanghai, China.
  • 3 Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
  • 4 Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China. guolei607@126.com.
  • 5 Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China. lf_deng@126.com.
  • 6 Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China. changwei393331@163.com.
PMID: 30626891 DOI: 10.1038/s41374-018-0175-8
Abstract

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.

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