Science (New York, N.Y.) · 2023
Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity.
СтатьяНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.