Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity
成果类型：
Article
署名作者：
Zhai, Yue; Chen, Liang; Zhao, Qian; Zheng, Zhao-Hui; Chen, Zhi-Nan; Bian, Huijie; Yang, Xu; Lu, Huan-Yu; Lin, Peng; Chen, Xi; Chen, Ruo; Sun, Hao-Yang; Fan, Lin-Ni; Zhang, Kun; Wang, Bin; Sun, Xiu-Xuan; Feng, Zhuan; Zhu, Yu-Meng; Zhou, Jian-Sheng; Chen, Shi-Rui; Zhang, Tao; Chen, Si-Yu; Chen, Jun-Jie; Zhang, Kui; Wang, Yan; Chang, Yang; Zhang, Rui; Zhang, Bei; Wang, Li-Juan; Li, Xiao-Min; He, Qian; Yang, Xiang-Min; Nan, Gang; Xie, Rong-Hua; Yang, Liu; Yang, Jing-Hua; Zhu, Ping
署名单位：
Air Force Medical University; Air Force Medical University; Shanghai University; Zhengzhou University; Air Force Medical University; Air Force Medical University; Air Force Medical University; Air Force Medical University
刊物名称：
SCIENCE
ISSN/ISSBN：
0036-13931
DOI：
10.1126/science.abg2482
发表日期：
2023-03-17
页码：
1104-+
关键词：
cystathionine beta-synthase
revised criteria
immune-system
association
cells
CLASSIFICATION
homeostasis
population
activation
expression
摘要：
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 aIIb [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.