Increased SUMO-activating enzyme SAE1/UBA2 promotes glycolysis and pathogenic behavior of rheumatoid fibroblast-like synoviocytes.
Increased SUMO-activating enzyme SAE1/UBA2 promotes glycolysis and pathogenic behavior of rheumatoid fibroblast-like synoviocytes.
复制标题
DOI：
10.1172/jci.insight.135935
复制
发表时间：
2020-09-17
期刊：
影响因子：
8
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Wang C;Xiao Y;Lao M;Wang J;Xu S;Li R;Xu X;Kuang Y;Shi M;Zou Y;Wang Q;Liang L;Zheng SG;Xu H
成纤维细胞样滑膜细胞（FLS）在类风湿关节炎（RA）的关节炎症和破坏中起着关键作用。RA FLS中糖酵解增加导致持续性关节损伤。SUMO化是一种蛋白质翻译后修饰，在许多疾病的发生发展中起着重要作用。然而，小泛素样修饰物激活酶1（SAE 1）/泛素样修饰物激活酶2（UBA 2）在调节致病性FLS行为中的作用尚不清楚。在这里，我们发现了增加的表达SAE 1和UBA 2在FLS和滑膜组织RA患者。通过siRNA敲低SAE 1或UBA 2并用GA（SAE 1/UBA 2介导的SUMO化的抑制剂）处理导致糖酵解减少、侵袭性表型和炎症。SAE 1/UBA 2介导的丙酮酸激酶M2（PKM 2）SUMO化促进其磷酸化和核转位，降低PK活性。此外，抑制PKM 2磷酸化增加PK活性并抑制糖酵解、侵袭性表型和炎症。我们进一步证明了STAT 5A介导SUMO化PKM 2诱导的糖酵解和生物学行为。有趣的是，GA治疗减轻了胶原诱导关节炎小鼠和人TNF-α转基因小鼠关节炎的严重程度。这些发现表明，滑膜中SAE 1/UBA 2的增加可能有助于RA的滑膜糖酵解和关节炎症，靶向SAE 1/UBA 2可能对RA患者具有治疗潜力。SUMO激活酶SAE 1/UBA 2通过丙酮酸激酶M2的SUMO化促进类风湿成纤维细胞样滑膜细胞的糖酵解和致病行为
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. SUMO-activating enzyme SAE1/UBA2 promotes glycolysis and pathogenic behavior of rheumatoid fibroblast-like synoviocytes through SUMOylation of pyruvate kinase M2.