清华大学刘万里等研究人员合作发现，逐步的聚腺苷酸化和m⁶A修饰维持抗体分泌细胞中IgG1抗体的稳态。相关论文于2024年10月29日在线发表在《免疫》杂志上。

研究人员发现mRNA的聚腺苷酸化和N6-甲基腺苷（m⁶A）修饰在维持IgG1抗体的产生中发挥重要作用。IgG重链转录本（Ighg）具有长的3' UTR，并包含m⁶A位点，且这些位点被m6A读取蛋白YTHDF1靶向。B细胞特异性缺失YTHDF1会在抗原免疫接种后减少IgG1⁺ 抗体分泌细胞（ASC）中Ighg1 mRNA的丰度，从而损害IgG的产生。

破坏核内剪接中间体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测序识别出一种在系统性红斑狼疮患者中YTHDF1表达过高的ASC亚群，且在免疫抑制药物治疗后减少。在狼疮小鼠模型中，抑制YTHDF1与m⁶A的相互作用缓解了症状。

因此，该研究强调了ASC中通过整合Ighg1 mRNA的聚腺苷酸化和m⁶A修饰来维持IgG抗体转录本稳态的机制。

研究人员表示，抗原特异性抗体由ASC生成。然而，RNA转录后修饰如何影响抗体稳态仍不清楚。

附：英文原文

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

Author: 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

Issue&Volume: 2024-10-29

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 (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.

DOI: 10.1016/j.immuni.2024.10.004

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00484-9