CCCTC-binding factor: the specific transcription factor of β-galactoside α-2,6-sialyltransferase 1 that upregulates the sialylation of anti-citrullinated protein antibodies in rheumatoid arthritis
CCCTC-binding factor: the specific transcription factor of β-galactoside α-2,6-sialyltransferase 1 that upregulates the sialylation of anti-citrullinated protein antibodies in rheumatoid arthritis
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DOI：
10.1093/rheumatology/kead282
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发表时间：
2023-06-16
期刊：
影响因子：
5.5
通讯作者：
Wang，Jianguang
中科院分区：
文献类型：
--
作者：
Zhao，Heping;Wang，Hao;Wang，Jianguang
β-半乳糖苷α-2，6-唾液酸转移酶1（β-galactoside α-2，6-sialyltransferase 1，ST 6 GAL 1）催化ACPAs的可结晶片段（crystallisable fragment，Fc）的唾液酸化可减轻RA的炎症反应。本研究通过筛选ST 6 GAL 1的转录因子，阐明其上调B细胞ACPAs唾液酸化的机制，探讨其在RA发病中的作用通过LC-MS/MS分析，并通过染色质免疫沉淀（ChIP）、双荧光素酶报告基因测定和电泳迁移率变动测定（EMSA）进行验证。通过在B细胞中敲低和过表达CCCTC结合因子（CTCF）来验证CTCF对ST 6 GAL 1表达的作用以及ACPA的炎症效应。CIA模型构建从B细胞特异性CTCF基因敲除小鼠，探讨CTCF对关节炎progress.ResultsWe观察到，在RA患者的血清中的ST 6 GAL 1和ACPAs唾液酸化水平下降，并与DAS 28评分呈负相关。随后，CTCF被筛选并验证为与ST 6 GAL 1的P2启动子相互作用的转录因子，其增强ACPAs的唾液酸化，从而减弱ACPAs的炎症活性。结论CCCTC结合因子是B细胞β-半乳糖苷α-2，6-唾液酸转移酶1的特异性转录因子，可上调RA患者ACPAs的唾液酸化，抑制RA的进展。
ObjectiveSialylation of the crystallizable fragment (Fc) of ACPAs, which is catalysed by β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) could attenuate inflammation of RA. In this study, we screened the transcription factor ofST6GAL1and elucidated the mechanism of transcriptionally upregulating sialylation of ACPAs in B cells to explore its role in the progression of RA.MethodsTranscription factors interacting with the P2 promoter ofST6GAL1were screened by DNA pull-down and liquid chromatography with tandem mass spectrometry (LC-MS/MS), and verified by chromatin immunoprecipitation (ChIP), dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The function of the CCCTC-binding factor (CTCF) on the expression ofST6GAL1and the inflammatory effect of ACPAs were verified by knocking down and overexpressing CTCF in B cells. The CIA model was constructed from B cell–specific CTCF knockout mice to explore the effect of CTCF on arthritis progression.ResultsWe observed that the levels of ST6GAL1 and ACPAs sialylation decreased in the serum of RA patients and were negatively correlated with DAS28 scores. Subsequently, CTCF was screened and verified as the transcription factor interacting with the P2 promoter of ST6GAL1, which enhances the sialylation of ACPAs, thus weakening the inflammatory activity of ACPAs. Furthermore, the above results were also verified in the CIA model constructed from B cell–specific CTCF knockout mice.ConclusionCCCTC-binding factor is the specific transcription factor of β-galactoside α-2,6-sialyltransferase 1 in B cells that upregulates the sialylation of ACPAs in RA and attenuates the disease progression.