Department of Microbiology, Immunology and Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX 78229, USA.
Sci Adv. 2020 Apr 1;6(14):eaay2793. doi: 10.1126/sciadv.aay2793. eCollection 2020 Apr.
Activation-induced cytidine deaminase (AID) mediates immunoglobulin class switch DNA recombination (CSR) and somatic hypermutation (SHM), critical processes for maturation of the antibody response. Epigenetic factors, such as histone deacetylases (HDACs), would underpin B cell differentiation stage-specific AID expression. Here, we showed that NAD-dependent class III HDAC sirtuin 1 (Sirt1) is highly expressed in resting B cells and down-regulated by stimuli inducing AID. B cell Sirt1 down-regulation, deprivation of NAD cofactor, or genetic Sirt1 deletion reduced deacetylation of promoter histones, Dnmt1, and nuclear factor-κB (NF-κB) p65 and increased AID expression. This promoted class-switched and hypermutated T-dependent and T-independent antibody responses or led to generation of autoantibodies. Genetic Sirt1 overexpression, Sirt1 boost by NAD, or allosteric Sirt1 enhancement by SRT1720 repressed AID expression and CSR/SHM. By deacetylating histone and nonhistone proteins (Dnmt1 and NF-κB p65), Sirt1 transduces metabolic cues into epigenetic changes to play an important B cell-intrinsic role in modulating antibody and autoantibody responses.
激活诱导胞嘧啶脱氨酶 (AID) 介导免疫球蛋白类别转换 DNA 重组 (CSR) 和体细胞高频突变 (SHM)，这是抗体反应成熟的关键过程。表观遗传因素，如组蛋白去乙酰化酶 (HDACs)，将为 B 细胞分化阶段特异性 AID 表达提供基础。在这里，我们表明 NAD 依赖性 III 类 HDACs 沉默调节因子 1 (Sirt1) 在静止 B 细胞中高度表达，并被诱导 AID 的刺激下调。B 细胞 Sirt1 下调、NAD 辅助因子缺失或基因 Sirt1 缺失会降低启动子组蛋白、Dnmt1 和核因子-κB (NF-κB) p65 的去乙酰化，并增加 AID 的表达。这促进了类别转换和高频突变的 T 依赖性和 T 非依赖性抗体反应，或导致自身抗体的产生。基因 Sirt1 过表达、NAD 增强 Sirt1 或 SRT1720 的别构增强会抑制 AID 表达和 CSR/SHM。Sirt1 通过去乙酰化组蛋白和非组蛋白蛋白 (Dnmt1 和 NF-κB p65) 将代谢信号转导为表观遗传变化，在调节抗体和自身抗体反应方面发挥重要的 B 细胞固有作用。
