Methionine Commits Cells to Differentiate Into Plasmablasts Through Epigenetic Regulation of BTB and CNC Homolog 2 by the Methyltransferase EZH2.

Abstract

Plasmablasts play important roles in autoimmune diseases, including systemic lupus erythematosus (SLE). Activation of mechanistic target of rapamycin complex 1 (mTORC1) is regulated by amino acid levels. In patients with SLE, mTORC1 is activated in B cells and modulates plasmablast differentiation. However, the detailed mechanisms of amino acid metabolism in plasmablast differentiation remain elusive. We undertook this study to evaluate the effects of methionine in human B cells. Purified CD19+ cells from healthy donors (n = 21) or patients with SLE (n = 35) were cultured with Toll-like receptor 7/9 ligand, interferon-α (IFNα), and B cell receptor crosslinking, and we determined the types of amino acids that were important for plasmablast differentiation and amino acid metabolism. We also identified the transcriptional regulatory mechanisms induced by amino acid metabolism, and we assessed B cell metabolism and its relevance to SLE. The essential amino acid methionine strongly committed cells to plasmablast differentiation. In the presence of methionine, Syk and mTORC1 activation synergistically induced methyltransferase EZH2 expression. EZH2 induced H3K27me3 at BTB and CNC homolog 2 (Bach2) loci and suppressed Bach2 expression, leading to induction of B lymphocyte-induced maturation protein 1 and X-box binding protein 1 expression and plasmablast differentiation. CD19+ cells from patients with SLE overexpressed EZH2, which was correlated with disease activity and autoantibody production. Our findings show that methionine activated signaling by controlling immunologic metabolism in B cells and played an important role in the differentiation of B cells into plasmablasts through epigenome modification of Bach2 by the methyltransferase EZH2.