The nuclear role of methionine adenosyltransferase 2A in immunoglobulin class switch recombination

Methionine adenosyltransferase synthesizes S-adenosylmethionine (SAM), the universal methyl donor. Its ubiquitous isozyme MAT2 is present in the nucleus and regulates gene expression through histone methylation. However, the physiological significance of its nuclear enzymatic activity remains unclear. Here, we investigate the role of nuclear MAT2 in antibody class switch recombination (CSR), a crucial process in adaptive immunity. We established murine B-cell lines expressing either wild-type (WT) or catalytically-inactive (D134A) MAT2A subunits, targeted to the nucleus with nuclear localization signal (NLS). Inhibition of nuclear MAT2 enzymatic activity by expressing NLS-MAT2A(D134A) significantly suppressed CSR from IgM to IgA and reduced intracellular SAM levels. Chromatin immunoprecipitation revealed that MAT2A localized to the IgA switch region. Interestingly, while the expression of germline transcripts was enhanced, the expression of activation-induced cytidine deaminase (AID), an essential enzyme for CSR, was downregulated in NLS-MAT2A(D134A) cells. Our findings demonstrate that the enzymatic activity of MAT2 in the nucleus is indispensable for CSR, likely by ensuring proper AID expression subsequent to germline transcription, thus revealing a critical link between nuclear SAM metabolism and adaptive immunity.