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

IF 25.5 1区 医学 Q1 IMMUNOLOGY
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
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引用次数: 0

摘要

抗原特异性抗体由抗体分泌细胞(ASCs)产生。RNA转录后修饰如何影响抗体稳态仍不清楚。在这里,我们发现mRNA多腺苷酸化和N6-甲基腺苷(m6A)修饰能维持ASCs中IgG1抗体的产生。IgG 重链转录本(Ighg)具有长的 3′ UTR,带有 m6A 位点,是 m6A 阅读器 YTHDF1 的靶标。B 细胞特异性缺乏 YTHDF1 会降低 IgG1+ ASCs 中 Ighg1 mRNA 的丰度,从而影响抗原免疫后 IgG 的产生。破坏核定位剪接中间体Ighg1的m6A修饰或YTHDF1的核定位都会降低Ighg1转录本的稳定性。单细胞 RNA 测序确定了系统性红斑狼疮患者中 YTHDF1 过度表达的 ASC 亚群,该亚群在接受免疫抑制剂治疗后表达减少。在狼疮小鼠模型中,抑制 YTHDF1-m6A 的相互作用可减轻症状。因此,我们强调了ASCs中通过整合Ighg1 mRNA多腺苷酸化和m6A修饰来维持IgG抗体转录本平衡的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Progressive polyadenylation and m6A modification of Ighg1 mRNA maintain IgG1 antibody homeostasis in antibody-secreting cells

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.
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来源期刊
Immunity
Immunity 医学-免疫学
CiteScore
49.40
自引率
2.20%
发文量
205
审稿时长
6 months
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.
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