Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity
Yue Zhai, Liang Chen, Qian Zhao, Zhaohui Zheng, Zhi‐Nan Chen, Huijie Bian, Xu Yang, Xu Yang, Huanyu Lu, Lin Peng, Xi Chen, Ruo Chen, Haoyang Sun, Linni Fan, Kun Zhang, Bin Wang, Xiuxuan Sun, Zhuan Feng, Yumeng Zhu, Jiansheng Zhou, Shirui Chen, Tao� Zhang, Siyu Chen, Junjie Chen, Kui Zhang, Yan Wang, Yang Chang, Rui Zhang, Bei Zhang, Lijuan Wang, Xiaomin Li, Qian He, Xiang-Min Yang, Xiang-Min Yang, Gang Nan, Xie Rong-hua, Yang Liu, Jing-Hua Yang, Ping Zhu
Abstract
Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4 + T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4 + T cell responses and autoantibody production in autoimmune diseases.