A qualitative proteome-wide lysine crotonylation profiling reveals protein modification alteration in the leukocyte extravasation pathway in systemic lupus erythematosus

Background Systemic lupus erythematosus (SLE) is a severe systemic autoimmune disease with multiple manifestations. Lysine crotonylation (Kcr) is a newly discovered post-translational modification (PTM) epigenetic pattern which may affect gene expression and linked to diseases causally. Methods We collected blood samples from 11 SLE individuals and 36 healthy subjects. Then we used highly sensitive liquid chromatography-mass spectrometry technology to carry out proteomics and quantitative crotonylome analysis of SLE peripheral blood mononuclear cells in this investigation, which indicated the unique etiology of SLE. Results There were 618 differentially expressed proteins (DEPs), and 612 crotonylated lysine sites for 272 differentially modified proteins (DMPs) found. According to KEGG analysis and ingenuity pathway analysis, these DEPs and DMPs are primarily enriched in the leukocyte extravasation signaling pathway. Conclusions This is the first study of crotonylated modification proteomics in SLE. The leukocyte extravasation signaling pathway had a considerable concentration of DEPs and DMPs, indicating that this pathway may be involved in the pathogenic development of SLE.

背景
系统性红斑狼疮（Systemic lupus erythematosus, SLE）是一种多系统受累的重症自身免疫性疾病。赖氨酸巴豆酰化（Lysine crotonylation, Kcr）是新近发现的翻译后修饰（post-translational modification, PTM）类表观遗传调控模式，可调控基因表达，并与疾病发生存在因果关联。
方法
本研究收集了11名系统性红斑狼疮患者与36名健康受试者的血液样本，采用高灵敏度液相色谱-质谱联用技术，对系统性红斑狼疮患者外周血单个核细胞开展蛋白质组学与定量巴豆酰化修饰组学分析，以此解析该病的特有发病机制。
结果
本研究共鉴定得到618个差异表达蛋白（differentially expressed proteins, DEPs），以及272个差异修饰蛋白（differentially modified proteins, DMPs）上的612个巴豆酰化赖氨酸位点。通过京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）富集分析与Ingenuity通路分析（Ingenuity Pathway Analysis, IPA），上述差异表达蛋白与差异修饰蛋白主要富集于白细胞渗出信号通路（leukocyte extravasation signaling pathway）。
结论
本研究首次针对系统性红斑狼疮开展巴豆酰化修饰蛋白质组学研究。白细胞渗出信号通路中富集了大量差异表达蛋白与差异修饰蛋白，提示该通路可能参与系统性红斑狼疮的致病进程。