Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, Guangdong, 515041, China.
College of Basic Medical Science, Dalian Medical University, 9-Western Section, Lvshun South Road, Dalian, Liaoning, 116044, China.
Adv Sci (Weinh). 2023 Sep;10(26):e2302607. doi: 10.1002/advs.202302607. Epub 2023 Jul 9.
α2,6-sialylation, catalyzed by α2,6-sialyltransferase (ST6GAL1), plays a pivotal role in immune responses. However, the role of ST6GAL1 in the pathogenesis of ulcerative colitis (UC) remains unknown. ST6GAL1 mRNA is highly expressed in UC tissues compared with the corresponding adjacent normal tissues, and α2,6-sialylation is significantly increased in the colon tissues of patients with UC. The expression of ST6GAL1 and proinflammatory cytokines, such as interleukin (IL)-2, IL-6, IL-17, and interferon-gamma, is also increased. The number of CD4 T cells increases in UC patients. St6gal1 gene knockout (St6gal1 ) rats are established by clustered regularly interspaced short palindromic repeats (CRISPR)-associated gene knockout system. St6gal1 deficiency reduces the levels of pro-inflammatory cytokines and alleviates colitis symptoms in UC model rats. Ablation of α2,6-sialylation inhibits the transport of the TCR to lipid rafts and suppresses CD4 T-cell activation. The attenuation of TCR signaling downregulates the expression of NF-κB in ST6GAL CD4 T-cells. Moreover, NF-κB could bind to the ST6GAL1 promoter to increase its transcription. Ablation of ST6GAL1 downregulates the expression of NF-κB and reduces the production of proinflammatory cytokines to relieve UC pathogenesis, which is a potential novel target for the clinical treatment of UC.
α2,6-唾液酸化作用，由 α2,6-唾液酸转移酶（ST6GAL1）催化，在免疫反应中起着关键作用。然而，ST6GAL1 在溃疡性结肠炎（UC）发病机制中的作用尚不清楚。与相应的相邻正常组织相比，UC 组织中 ST6GAL1 mRNA 表达水平较高，UC 患者结肠组织中的α2,6-唾液酸化作用显著增加。ST6GAL1 的表达和促炎细胞因子，如白细胞介素（IL）-2、IL-6、IL-17 和干扰素-γ，也增加。UC 患者的 CD4 T 细胞数量增加。通过聚类规则间隔短回文重复（CRISPR）相关基因敲除系统建立了 ST6GAL1 基因敲除（St6gal1 ）大鼠。ST6GAL1 缺乏可降低促炎细胞因子水平并减轻 UC 模型大鼠的结肠炎症状。α2,6-唾液酸化作用的缺失抑制了 TCR 向脂筏的转运并抑制了 CD4 T 细胞的激活。TCR 信号的衰减下调了 ST6GAL CD4 T 细胞中 NF-κB 的表达。此外，NF-κB 可以结合到 ST6GAL1 启动子上，增加其转录。ST6GAL1 的缺失下调了 NF-κB 的表达并减少了促炎细胞因子的产生，从而缓解 UC 的发病机制，这是 UC 临床治疗的一个潜在新靶点。
