受 Ca2+ 流入调控的 Circ-CAMTA1 可抑制丙酮酸羧化酶活性并调节系统性红斑狼疮患者的 T 细胞功能

IF 4.9 2区 医学 Q1 Medicine Arthritis Research & Therapy Pub Date : 2024-10-29 DOI:10.1186/s13075-024-03422-6
Hui-Chun Yu, Hsien-Yu Huang Tseng, Hsien-Bin Huang, Ming-Chi Lu
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引用次数: 0

摘要

研究系统性红斑狼疮(SLE)患者T细胞中Ca2+流入调控的环状RNA(circRNA)的作用。通过新一代测序分析了与离子霉素共培养和未与离子霉素共培养的 Jurkat 细胞中 circRNAs 的表达谱,并使用实时聚合酶链反应进行了验证。在 42 名系统性红斑狼疮患者和 23 名健康对照者的 T 细胞中进一步检测了已确定的 Ca2+ 流入调控的 circRNA。我们使用转染和 RNA 牵引试验研究了特定 circRNA 的生物功能。经过验证,我们证实在 Ca2+ 流入后,Jurkat 细胞中 circ-ERCC4、circ-NFATC2、circ-MYH10、circ-CAMTA1、circ-ASH1L、circ-SOCS7 和 circ-ASAP1 的表达水平持续上升。在系统性红斑狼疮患者的 T 细胞中,circ-CAMTA1、circ-ASH1L 和 circ-ASAP1 的表达水平明显较低,而在疾病活动度较高的患者中,其表达水平甚至更低。研究发现,干扰素(IFN)-α能抑制circ-CAMTA1的表达。circ-CAMTA1 与丙酮酸羧化酶结合,抑制其生物活性。过量表达 circ-CAMTA1(而非其线性形式)可显著降低细胞外葡萄糖水平。此外,circ-CAMTA1(而非其线性形式)的表达增加会降低 miR-181c-5p 的表达,从而导致 IL-2 分泌增加。在系统性红斑狼疮患者的 T 细胞中,三种受 Ca2+ 流入调节的 circ-RNAs - circ-CAMTA1、circ-ASH1L 和 circ-ASAP1 - 显著减少,并与疾病活动相关。IFN-α 抑制了 circ-CAMTA1 的表达,而 circ-CAMTA1 与丙酮酸羧化酶相互作用,抑制了其活性,影响了葡萄糖代谢,并增加了 IL-2 的分泌。这些研究结果表明,Ca²⁺的流入调节了系统性红斑狼疮患者T细胞的功能。
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Circ-CAMTA1 regulated by Ca2+ influx inhibited pyruvate carboxylase activity and modulate T cell function in patients with systemic lupus erythematosus
To investigate the roles of Ca2+ influx-regulated circular RNAs (circRNAs) in T cells from patients with systemic lupus erythematosus (SLE). The expression profile of circRNAs in Jurkat cells, co-cultured with and without ionomycin, was analyzed by next-generation sequencing and validated using real-time polymerase chain reaction. The identified Ca2+ influx-regulated circRNAs were further examined in T cells from 42 patients with SLE and 23 healthy controls. The biological function of specific circRNA was investigated using transfection and RNA pull-down assay. After validation, we confirmed that the expression levels of circ-ERCC4, circ-NFATC2, circ-MYH10, circ-CAMTA1, circ-ASH1L, circ-SOCS7, and circ-ASAP1 were consistently increased in Jurkat cells following Ca2+ influx. The expression levels of circ-CAMTA1, circ-ASH1L, and circ-ASAP1 were significantly lower in T cells from patients with SLE, with even lower levels observed in those with higher disease activity. Interferon (IFN)-α was found to suppress the expression of circ-CAMTA1. Circ-CAMTA1 bound to pyruvate carboxylase and inhibited its biological activity. Overexpression of circ-CAMTA1, but not its linear form, significantly decreased extracellular glucose levels. Furthermore, increased expression of circ-CAMTA1, but not its linear form, decreased miR-181c-5p expression, resulting increased IL-2 secretion. Three Ca2+ influx-regulated circ-RNAs—circ-CAMTA1, circ-ASH1L, and circ-ASAP1 —were significantly reduced in T cells from patients with SLE and associated with disease activity. IFN-α suppressed the expression of circ-CAMTA1, which interacted with pyruvate carboxylase, inhibited its activity, affected glucose metabolism, and increased IL-2 secretion. These findings suggest that circ-CAMTA1 regulated by Ca²⁺ influx modulated T cell function in patients with SLE.
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来源期刊
CiteScore
8.60
自引率
2.00%
发文量
261
审稿时长
14 weeks
期刊介绍: Established in 1999, Arthritis Research and Therapy is an international, open access, peer-reviewed journal, publishing original articles in the area of musculoskeletal research and therapy as well as, reviews, commentaries and reports. A major focus of the journal is on the immunologic processes leading to inflammation, damage and repair as they relate to autoimmune rheumatic and musculoskeletal conditions, and which inform the translation of this knowledge into advances in clinical care. Original basic, translational and clinical research is considered for publication along with results of early and late phase therapeutic trials, especially as they pertain to the underpinning science that informs clinical observations in interventional studies.
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