RNA 编辑酶 APOBEC3A 促进促炎 M1 巨噬细胞极化。
RNA editing enzyme APOBEC3A promotes pro-inflammatory M1 macrophage polarization.
机构信息
Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14203, USA.
Department of Pathology, Faculty of Medicine, Jazan University, Jazan, 45142, Saudi Arabia.
出版信息
Commun Biol. 2021 Jan 22;4(1):102. doi: 10.1038/s42003-020-01620-x.
Pro-inflammatory M1 macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C > U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections in normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of nonsynonymous RNA editing alters a highly-conserved amino acid in THOC5, which encodes a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-α, IL-1β and IL-6 cytokine secretion, and increases glycolysis. These results show a key role of APOBEC3A cytidine deaminase in transcriptomic and functional polarization of M1 macrophages.
促炎 M1 巨噬细胞极化与杀菌和抗肿瘤反应有关。我们最近描述了 M1 极化过程中 APOBEC3A 介导的胞嘧啶到尿嘧啶（C > U）RNA 编辑。然而，这种编辑的功能意义尚不清楚。在这里，我们发现 APOBEC3A 介导的细胞 RNA 编辑也可以被流感或马利巴病毒感染正常人类巨噬细胞以及肿瘤相关巨噬细胞中的干扰素诱导。基因敲低和 RNA_Seq 分析表明，APOBEC3A 在 M1 极化过程中介导 203 个基因的 209 个外显子/UTR 位点的 C > U RNA 编辑。非同义 RNA 编辑水平最高的是在 THOC5 中改变一个高度保守的氨基酸，该基因编码一种核 mRNA 输出蛋白，与 M-CSF 驱动的巨噬细胞分化有关。APOBEC3A 的敲低降低了 IL6、IL23A 和 IL12B 基因的表达、CD86 表面蛋白的表达以及 TNF-α、IL-1β 和 IL-6 细胞因子的分泌，并增加了糖酵解。这些结果表明 APOBEC3A 胞嘧啶脱氨酶在 M1 巨噬细胞的转录组和功能极化中起关键作用。
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