Increased SUMO-activating enzyme SAE1/UBA2 promotes glycolysis and pathogenic behavior of rheumatoid fibroblast-like synoviocytes.

Yaoyao Zou,Maohua Shi,Hanshi Xu,Minxi Lao,Song Guo Zheng,Ruiru Li,Jingnan Wang,Siqi Xu,Cuicui Wang,Yu Kuang,Liuqin Liang,Youjun Xiao,Qingwen Wang,Xuanxian Xu

doi:10.1172/jci.insight.135935

Abstract

Fibroblast-like synoviocytes (FLSs) are critical to joint inflammation and destruction in rheumatoid arthritis (RA). Increased glycolysis in RA FLSs contributes to persistent joint damage. SUMOylation, a posttranslational modification of proteins, plays an important role in initiation and development of many diseases. However, the role of small ubiquitin-like modifier–activating (SUMO-activating) enzyme 1 (SAE1)/ubiquitin like modifier activating enzyme 2 (UBA2) in regulating the pathogenic FLS behaviors is unknown. Here, we found an increased expression of SAE1 and UBA2 in FLSs and synovial tissues from patients with RA. SAE1 or UBA2 knockdown by siRNA and treatment with GA, an inhibitor of SAE1/UBA2-mediated SUMOylation, resulted in reduced glycolysis, aggressive phenotype, and inflammation. SAE1/UBA2-mediated SUMOylation of pyruvate kinase M2 (PKM2) promoted its phosphorylation and nuclear translocation and decreased PK activity. Moreover, inhibition of PKM2 phosphorylation increased PK activity and suppressed glycolysis, aggressive phenotype, and inflammation. We further demonstrated that STAT5A mediated SUMOylated PKM2-induced glycolysis and biological behaviors. Interestingly, GA treatment attenuated the severity of arthritis in mice with collagen-induced arthritis and human TNF-α transgenic mice. These findings suggest that an increase in synovial SAE1/UBA2 may contribute to synovial glycolysis and joint inflammation in RA and that targeting SAE1/UBA2 may have therapeutic potential in patients with RA.

Highlights

Rheumatoid arthritis (RA) is an autoimmune-mediated inflammatory disease characterized by progressive synovial inflammation and joint destruction
We found that SUMO-activating enzyme 1 (SAE1) and ubiquitin like modifier activating enzyme 2 (UBA2) expression was increased in Fibroblast-like synoviocytes (FLSs) from patients with RA compared with healthy controls (HCs) (Figure 1, A and B)
We evaluated the subcellular distribution of SAE1 and UBA2 in FLSs by immunofluorescence and found that RA FLSs exhibited markedly enhanced staining for these proteins (Figure 1C)

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune-mediated inflammatory disease characterized by progressive synovial inflammation and joint destruction. Fibroblast-like synoviocytes (FLSs), the predominant resident cells in the synovial lining, contribute to both rheumatoid synovial inflammation and joint damage. Increasing evidence suggests that targets for prevention of the activation and invasion of FLSs may be promising for ameliorating joint damage in RA [3,4,5]. Targeting glucose metabolism reprogramming may be a promising strategy for new therapeutics of many diseases, including cancer and autoimmune disorders [6,7,8]. It has been shown that glycolytic metabolism is especially enhanced in synovial tissues from patients with RA and contributes to persistent synovial inflammation and joint damage [9,10,11]. The underlying mechanisms that control the glycolytic metabolic phenotype of RA FLSs need to be defined

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