Department of Nephropathy and Rheumatology, the 3rd Xiangya Hospital, Central South University, Changsha, China.
Xiangya School of Medicine, Central South University, Changsha, China.
Cell Death Dis. 2021 Oct 30;12(11):1036. doi: 10.1038/s41419-021-04323-1.
Previous studies demonstrated that cGAS pathway is related to the inflammation amplification in a variety of autoimmune diseases. Lysine acetyltransferase family (KATs) can regulate the nuclear transcription or cytoplasmic activation of cGAS through different mechanisms. However, its role and related immunity patterns in systemic lupus erythematosus (SLE) have not been explored. In this study, RNA-seq and scRNA-seq profiling were performed for peripheral blood mononuclear cells (PBMCs) from patients with SLE. R packages were used for bioinformatic analysis. Cell culture, RT-PCR, western blotting, immunofluorescence, immunohistochemistry, and ELISA were used to explore gene expression in vitro or clinical specimens. Plasmid transfection and mass spectrometry were used to detect protein modifications. Eight acetyltransferase and deacetylase family members with significantly differential expression in SLE were found. Among them, KAT2A was abnormally upregulated and positively correlated with disease activity index. Further, KAT2A-cGAS pathway was aberrantly expressed in specific immune cell subsets in SLE. In vitro studies showed KAT2A modulated cGAS through increasing expression and post-translational modification. Our research provides novel insights for accurately positioning specific immune-cell subgroups in which KAT2A-cGAS reaction mainly works and KAT2A regulation patterns.
先前的研究表明，cGAS 通路与多种自身免疫性疾病中的炎症放大有关。赖氨酸乙酰转移酶家族（KATs）可以通过不同的机制调节 cGAS 的核转录或细胞质激活。然而，其在系统性红斑狼疮（SLE）中的作用和相关免疫模式尚未得到探索。在这项研究中，对来自 SLE 患者的外周血单核细胞（PBMC）进行了 RNA-seq 和 scRNA-seq 分析。使用 R 包进行生物信息学分析。细胞培养、RT-PCR、western blot、免疫荧光、免疫组化和 ELISA 用于体外或临床标本中探索基因表达。质粒转染和质谱用于检测蛋白质修饰。发现 SLE 中 8 种乙酰转移酶和去乙酰化酶家族成员的表达存在显著差异。其中，KAT2A 异常上调，并与疾病活动指数呈正相关。此外，SLE 中特定免疫细胞亚群中存在 KAT2A-cGAS 通路异常表达。体外研究表明，KAT2A 通过增加表达和翻译后修饰来调节 cGAS。我们的研究为准确定位 KAT2A-cGAS 反应主要作用的特定免疫细胞亚群以及 KAT2A 调节模式提供了新的见解。
