Yu Wang, Shaocun Zhang, Na Kang, Lihui Dong, Haochen Ni, Sichen Liu, Siankang Chong, Zhenglin Ji, Zhengpeng Wan, Xiangjun Chen, Fei Wang, Yun Lu, Baidong Hou, Pei Tong, Hai Qi, Meng Michelle Xu, Wanli Liu
{"title":"Ighg1 mRNA 的渐进多腺苷酸化和 m6A 修饰维持抗体分泌细胞中 IgG1 抗体的稳态","authors":"Yu Wang, Shaocun Zhang, Na Kang, Lihui Dong, Haochen Ni, Sichen Liu, Siankang Chong, Zhenglin Ji, Zhengpeng Wan, Xiangjun Chen, Fei Wang, Yun Lu, Baidong Hou, Pei Tong, Hai Qi, Meng Michelle Xu, Wanli Liu","doi":"10.1016/j.immuni.2024.10.004","DOIUrl":null,"url":null,"abstract":"Antigen-specific antibodies are generated by antibody-secreting cells (ASCs). How RNA post-transcriptional modification affects antibody homeostasis remains unclear. Here, we found that mRNA polyadenylations and N6-methyladenosine (m6A) modifications maintain IgG1 antibody production in ASCs. IgG heavy-chain transcripts (<em>Ighg</em>) possessed a long 3′ UTR with m6A sites, targeted by the m6A reader YTHDF1. B cell-specific deficiency of YTHDF1 impaired IgG production upon antigen immunization through reducing <em>Ighg1</em> mRNA abundance in IgG1<sup>+</sup> ASCs. Disrupting either the m6A modification of a nuclear-localized splicing intermediate <em>Ighg1</em> or the nuclear localization of YTHDF1 reduced <em>Ighg1</em> transcript stability. Single-cell RNA sequencing identified an ASC subset with excessive YTHDF1 expression in systemic lupus erythematosus patients, which was decreased upon therapy with immunosuppressive drugs. In a lupus mouse model, inhibiting YTHDF1-m6A interactions alleviated symptoms. Thus, we highlight a mechanism in ASCs to sustain the homeostasis of IgG antibody transcripts by integrating <em>Ighg1</em> mRNA polyadenylation and m6A modification.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":25.5000,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Progressive polyadenylation and m6A modification of Ighg1 mRNA maintain IgG1 antibody homeostasis in antibody-secreting cells\",\"authors\":\"Yu Wang, Shaocun Zhang, Na Kang, Lihui Dong, Haochen Ni, Sichen Liu, Siankang Chong, Zhenglin Ji, Zhengpeng Wan, Xiangjun Chen, Fei Wang, Yun Lu, Baidong Hou, Pei Tong, Hai Qi, Meng Michelle Xu, Wanli Liu\",\"doi\":\"10.1016/j.immuni.2024.10.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Antigen-specific antibodies are generated by antibody-secreting cells (ASCs). How RNA post-transcriptional modification affects antibody homeostasis remains unclear. Here, we found that mRNA polyadenylations and N6-methyladenosine (m6A) modifications maintain IgG1 antibody production in ASCs. IgG heavy-chain transcripts (<em>Ighg</em>) possessed a long 3′ UTR with m6A sites, targeted by the m6A reader YTHDF1. B cell-specific deficiency of YTHDF1 impaired IgG production upon antigen immunization through reducing <em>Ighg1</em> mRNA abundance in IgG1<sup>+</sup> ASCs. Disrupting either the m6A modification of a nuclear-localized splicing intermediate <em>Ighg1</em> or the nuclear localization of YTHDF1 reduced <em>Ighg1</em> transcript stability. Single-cell RNA sequencing identified an ASC subset with excessive YTHDF1 expression in systemic lupus erythematosus patients, which was decreased upon therapy with immunosuppressive drugs. In a lupus mouse model, inhibiting YTHDF1-m6A interactions alleviated symptoms. Thus, we highlight a mechanism in ASCs to sustain the homeostasis of IgG antibody transcripts by integrating <em>Ighg1</em> mRNA polyadenylation and m6A modification.\",\"PeriodicalId\":13269,\"journal\":{\"name\":\"Immunity\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":25.5000,\"publicationDate\":\"2024-10-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.immuni.2024.10.004\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.immuni.2024.10.004","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Progressive polyadenylation and m6A modification of Ighg1 mRNA maintain IgG1 antibody homeostasis in antibody-secreting cells
Antigen-specific antibodies are generated by antibody-secreting cells (ASCs). How RNA post-transcriptional modification affects antibody homeostasis remains unclear. Here, we found that mRNA polyadenylations and N6-methyladenosine (m6A) modifications maintain IgG1 antibody production in ASCs. IgG heavy-chain transcripts (Ighg) possessed a long 3′ UTR with m6A sites, targeted by the m6A reader YTHDF1. B cell-specific deficiency of YTHDF1 impaired IgG production upon antigen immunization through reducing Ighg1 mRNA abundance in IgG1+ ASCs. Disrupting either the m6A modification of a nuclear-localized splicing intermediate Ighg1 or the nuclear localization of YTHDF1 reduced Ighg1 transcript stability. Single-cell RNA sequencing identified an ASC subset with excessive YTHDF1 expression in systemic lupus erythematosus patients, which was decreased upon therapy with immunosuppressive drugs. In a lupus mouse model, inhibiting YTHDF1-m6A interactions alleviated symptoms. Thus, we highlight a mechanism in ASCs to sustain the homeostasis of IgG antibody transcripts by integrating Ighg1 mRNA polyadenylation and m6A modification.
期刊介绍:
Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.