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TRAF6 Neddylation Drives Inflammatory Arthritis by Increasing

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TRAF6 Neddylation Drives Inflammatory Arthritis by Increasing Laboratory Investigation (2019) 99:528–538 https://doi.org/10.1038/s41374-018-0175-8 ARTICLE TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation 1 1 2 3 1 1 1 1 Kewei Liu ● Kaizhe Chen ● Qian Zhang ● Lianfang Zhang ● Yufei Yan ● Changjun Guo ● Jin Qi ● Kai Yang ● 1 1 1 1 1 Fei Wang ● Ping Huang ● Lei Guo ● Lianfu Deng ● Changwei Li Received: 21 May 2018 / Revised: 20 October 2018 / Accepted: 6 November 2018 / Published online: 9 January 2019 © The Author(s) 2019. This article is published with open access 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 fi 1234567890();,: 1234567890();,: broblast-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. Introduction and cellular infiltration, often leads to bone erosion and cartilage destruction [1]. Significant therapeutic advances Rheumatoid arthritis (RA), an autoimmune and systemic have greatly improved the lives of patients with RA over the inflammatory disorder characterized by chronic synovitis last few decades [2]. In particular, treatment strategies tar- geting various cellular and molecular aspects of the immune system, such as B cells, T-cell co-stimulation, Janus kinase (Jak)-mediated cytokine signaling, and the cytokines tumor These authors contributed equally: Kewei Liu, Kaizhe Chen necrosis factor-α (TNF-α) and interleukin-6 (IL-6), have * proven to be highly effective in limiting synovial joint Lei Guo fl [email protected] in ammation as well as preventing irreversible joint and * Lianfu Deng cartilage destruction and hyper-proliferation of synovial [email protected] cells [3]. Despite this progress, not all patients with RA * Changwei Li respond to these therapies or they become resistant to these [email protected] therapies over time [4]. Thus, advancing the understanding of the underlying etiology is required for the development 1 Shanghai Key Laboratory for Prevention and Treatment of Bone of innovative therapies for treating RA. and Joint Diseases with Integrated Chinese-Western Medicine, Posttranslational modification by ubiquitin has been Shanghai Institute of Traumatology and Orthopedics, Ruijin demonstrated to be a critical mechanism regulating the Hospital, Shanghai Jiaotong University School of Medicine, 197 fl Ruijin 2nd Road, 200025 Shanghai, China pathogenesis of in ammatory arthritis [5]. The role of 2 particular modifications, such as phosphorylation in the NF- Department of Orthopedic Surgery, Guanghua Integrative κ fl Medicine Hospital, No.540 Xinhua Road, 200052 B pathway, and their role in the arthritis in ammatory Shanghai, China response have been extensively studied [6]. The ubiquitin κ 3 Department of Orthopedics, The First Affiliated Hospital of proteasome system (UPS) controls NF- B activity by reg- Soochow University, Suzhou, Jiangsu Province, China ulating the degradation of the inhibitory protein IκB, which TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation 529 results in the expression of many pivotal cytokine and chemokine mediators that contribute to the inflammation response in RA, including TNF-α, IL-6, IL-8, inducible nitric oxidase synthase, and cyclooxygenase-2 (COX-2) [7]. In preclinical animal models, inhibition of UPS effectively ameliorates arthritis symptoms by limiting the inflammatory response and suppressing synovium hyperplasia [5, 8]. Thus, the ubiquitin proteasome pathway could be a target for the treatment of inflammatory arthritis. Cullin-RING E3 ligases (CRLs) are a class of ubiquitin ligases that control the proteasomal degradation of numer- ous target proteins, including IκB[9]. Except for ubiquiti- nation, the activity of CRLs is positively regulated by the conjugation of an NEDD8 polypeptide onto cullin proteins in a process called neddylation [10, 11]. It is clear that NEDD8 modification of the Cul-1 component of ubiquitin ligase enzyme complex SCFβ-TrCP is important for the function of SCFβ-TrCP in ubiquitination of IkBα and NF-κB precursor p105 [12, 13]. Neddylation occurs through a series of enzymatic reactions similar to those involved in ubiquitination, including the E1 (NAE1/UBA3) and E2 (UBC12) reactions [14]. The well-characterized substrates that are modified by NEDD8 include the cullin subunits of CRLs; this modification of cullins is critical for the transfer of ubiquitin from E2-ubiquitin to the substrate [15, 16]. Recent studies have shown that the pharmacological agent MLN4924 can potently inhibit NEDD8-activating enzymes, thereby prohibiting the transfer of NEDD8 onto target proteins [9]. Except for cancer cell survival [17], the ned- Fig. 1 Neddylation activation-related genes expression is increased in fl fi Nedd8 dylation pathway has been demonstrated to play a critical in amed arthritic synovia. a, b Quanti cation analysis of and Cullin-1 mRNA expression in synovium of OA (n = 6) and RA (n = role in regulating the functions of B cells [18], T cells [14], 12). c immunohistochemical staining analysis of NEDD8 and Cullin-1 myeloid leukemia cells [19], macrophages [9], and endo- expression in synovium of OA (n = 6) and RA (n = 12). *P < 0.05, thelial cells [20] during inflammatory responses. Therefore, **P < 0.01. P values were analyzed by two-tailed t tests. Scale bar μ neddylation inhibitors could be used as potential anti- represents 50 m inflammatory agents. However, the role of neddylation in inflammatory arthritis is not well known. underwent total knee arthroplasty (TKA) surgery for end- Given that CRLs play a key role in the etiology of stage RA. Furthermore, synovial tissues isolated from six inflammatory arthritis, and that their activity is also posi- patients with noninflamed osteoarthritis (OA) who under- tively regulated by neddylation, here we investigated whe- went TKA were used as control [21]. RT-PCR revealed that ther neddylation is involved in the pathogenesis of CIA. mRNA levels of NEDD8 and CULLIN-1 were notably Our findings uncover a pathogenic role of neddylation in increased in the synovium of patients with RA compared to CIA and delineate a previously unknown mechanism that in patients with noninflamed OA (Fig. 1a, b). More- involved in its process. over, the upregulated expression of NEDD8 and CULLIN-1 in the inflamed arthritic synovia was further confirmed by immunohistochemical staining analysis (Fig. 1c). Collec- Results tively, these data demonstrated that inflammatory arthritis increased neddylation in the synovium. Neddylation is activated in inflamed arthritic synovia Inhibition of neddylation reduces the severity of collagen-induced arthritis To explore the role of neddylation in inflammatory arthritis, we first identified neddylation-related genes that were Next, we investigated the pathogenic role of neddylation in expressed in synovial tissues collected from 12 patients who the CIA model of RA. MLN4924 was used to attenuate 530 K. Liu et al. Fig. 2 Inhibition of neddylation reduces the severity of collagen- knee joints. g–i Quantification analysis of TNF-α, IL-6, and IL-17A induced arthritis. a, b Time curve of body weight and arthritis score. mRNA expression in the affected paws. *P < 0.05, **P < 0.01, c, d Visual inspection and X-ray analysis of affected hind limbs. e Pain ****P < 0.0001. P values were analyzed by two-way ANOVA in score of affected paws. f Synovium volume detected by MRI of the (a, b) and one-way ANOVA in (e–i) neddylation in this model. As shown in Fig. 2a, inhibition of in a notably milder synovial hyperplasia, as evidenced by the neddylation by MLN4924 markedly suppressed the weight decreased synovium volume detected by magnetic resonance loss induced by the intradermal injection of type II collagen. imaging (MRI) of the knee joints (Fig. 2f). In addition, the Likewise, administration of MLN4924 significantly ame- reduced expressions of TNF-α, IL-6, and IL-17A in the liorated severe swelling, erythema, and joint rigidity in the paws of the CIA model further confirmed the protective role hind paws, as indicated by arthritis scores (Fig. 2b), visual of MLN4924 in CIA (Fig. 2g–i). Taken together, these inspection (Fig. 2c), X-ray analysis (Fig. 2d), and pain results demonstrated that inhibition of neddylation reduced scores (Fig. 2e). Furthermore, MLN4924 treatment resulted the severity of CIA. TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation 531 Fig. 3 Inhibition of neddylation suppresses IL-17A-induced inflam-
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