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.

中文翻译：

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Ighg1 mRNA 的进行性聚腺苷酸化和 m6A 修饰维持抗体分泌细胞中的 IgG1 抗体稳态


抗原特异性抗体由抗体分泌细胞 （ASC） 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 多聚腺苷酸化和 N6-甲基腺苷 （m6A） 修饰可维持 ASC 中 IgG1 抗体的产生。IgG 重链转录本 （Ighg） 具有带有 m6A 位点的长 3′ UTR，被 m6A 读取器 YTHDF1 靶向。YTHDF1 的 B 细胞特异性缺陷通过降低 IgG1+ ASCs 中 Ighg1 mRNA 的丰度来损害抗原免疫时 IgG 的产生。破坏核定位剪接中间体 Ighg1 的 m6A 修饰或 YTHDF1 的核定位降低了 Ighg1 转录本的稳定性。单细胞 RNA 测序在系统性红斑狼疮患者中鉴定出 YTHDF1 表达过高的 ASC 亚群，在免疫抑制药物治疗后表达降低。在狼疮小鼠模型中，抑制 YTHDF1-m6A 相互作用可缓解症状。因此，我们强调了 ASC 中通过整合 Ighg1 mRNA 多聚腺苷酸化和 m6A 修饰来维持 IgG 抗体转录物稳态的机制。