Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity

Author:

Zhai Yue1ORCID,Chen Liang2ORCID,Zhao Qian3ORCID,Zheng Zhao-Hui1ORCID,Chen Zhi-Nan1ORCID,Bian Huijie1ORCID,Yang Xu1,Lu Huan-Yu4,Lin Peng1ORCID,Chen Xi1ORCID,Chen Ruo1,Sun Hao-Yang1,Fan Lin-Ni5ORCID,Zhang Kun1,Wang Bin1,Sun Xiu-Xuan1,Feng Zhuan1,Zhu Yu-Meng1,Zhou Jian-Sheng1ORCID,Chen Shi-Rui1,Zhang Tao1,Chen Si-Yu1,Chen Jun-Jie1,Zhang Kui1,Wang Yan1,Chang Yang1,Zhang Rui1,Zhang Bei1ORCID,Wang Li-Juan1,Li Xiao-Min1,He Qian1,Yang Xiang-Min1,Nan Gang1,Xie Rong-Hua1ORCID,Yang Liu1,Yang Jing-Hua13ORCID,Zhu Ping1ORCID

Affiliation:

1. Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi’an 710032, China.

2. School of Medicine, Shanghai University, Shanghai 200444, China.

3. Clinical Systems Biology Laboratories, Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China.

4. Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi’an 710032, China.

5. State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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