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. [Display omitted] • m6A-modified Ighg1 RNA acts as a precursor for secretory Ighg1 • Loss of YTHDF1 in B cells decreases IgG response by reducing IgG transcript life in ASCs • YTHDF1 and Ighg1 mRNA form nuclear granules for Ighg1 stability in ASCs • YTHDF1 accumulation in ASCs promotes the pathogenesis of SLE IgG antibody production must be tightly maintained for appropriate antibody immunity. Wang et al. reveal a mechanism to sustain the homeostasis of IgG antibody transcripts by integrating Ighg1 mRNA polyadenylation and m6A modification in antibody-secreting cells (ASCs). Data from individuals with SLE and from a lupus mouse model highlight the clinical relevance of the mechanism. [ABSTRACT FROM AUTHOR]