We aim to establish a comprehensive COVID-19 autoantigen atlas in order to understand autoimmune diseases caused by SARS-CoV-2 infection. Based on the unique affinity between dermatan sulfate and autoantigens, we identified 348 proteins from human lung A549 cells, of which 198 are known targets of autoantibodies. Comparison with current COVID data identified 291 proteins that are altered at protein or transcript level in SARS-CoV-2 infection, with 191 being known autoantigens. These known and putative autoantigens are significantly associated with viral replication and trafficking processes, including gene expression, ribonucleoprotein biogenesis, mRNA metabolism, translation, vesicle and vesicle-mediated transport, and apoptosis. They are also associated with cytoskeleton, platelet degranulation, IL-12 signaling, and smooth muscle contraction. Host proteins that interact with and that are perturbed by viral proteins are a major source of autoantigens. Orf3 induces the largest number of protein alterations, Orf9 affects the mitochondrial ribosome, and they and E, M, N, and Nsp proteins affect protein localization to membrane, immune responses, and apoptosis. Phosphorylation and ubiquitination alterations by viral infection define major molecular changes in autoantigen origination. This study provides a large list of autoantigens as well as new targets for future investigation, e.g., UBA1, UCHL1, USP7, CDK11A, PRKDC, PLD3, PSAT1, RAB1A, SLC2A1, platelet activating factor acetylhydrolase, and mitochondrial ribosomal proteins. This study illustrates how viral infection can modify host cellular proteins extensively, yield diverse autoantigens, and trigger a myriad of autoimmune sequelae. Our work provides a rich resource for studies into “long COVID” and related autoimmune sequelae.

我们的目标是建立一个全面的 COVID-19 自身抗原图谱，以了解由 SARS-CoV-2 感染引起的自身免疫性疾病。基于硫酸皮肤素与自身抗原之间独特的亲和力，我们从人肺 A549 细胞中鉴定出 348 种蛋白质，其中 198 种是已知的自身抗体靶标。与当前 COVID 数据的比较确定了 291 种蛋白质，这些蛋白质在 SARS-CoV-2 感染中在蛋白质或转录水平发生了改变，其中 191 种是已知的自身抗原。这些已知和推定的自身抗原与病毒复制和运输过程显着相关，包括基因表达、核糖核蛋白生物合成、mRNA 代谢、翻译、囊泡和囊泡介导的转运以及细胞凋亡。它们还与细胞骨架、血小板脱颗粒、IL-12 信号和平滑肌收缩有关。与病毒蛋白相互作用并受其干扰的宿主蛋白是自身抗原的主要来源。Orf3 诱导最大数量的蛋白质改变，Orf9 影响线粒体核糖体，它们和 E、M、N 和 Nsp 蛋白影响蛋白质定位到膜、免疫反应和细胞凋亡。病毒感染引起的磷酸化和泛素化改变定义了自身抗原起源的主要分子变化。该研究提供了大量自身抗原以及未来研究的新靶点，例如 UBA1、UCHL1、USP7、CDK11A、PRKDC、PLD3、PSAT1、RAB1A、SLC2A1、血小板活化因子乙酰水解酶和线粒体核糖体蛋白。这项研究说明了病毒感染如何广泛修饰宿主细胞蛋白，产生多种自身抗原，并引发无数自身免疫性后遗症。