Necessity of HuR/ELAVL1 for the activation-induced cytidine deaminase-dependent decrease in topoisomerase 1 in antibody diversification.

IF 4.8 4区 医学 Q2 IMMUNOLOGY International immunology Pub Date : 2023-08-07 DOI:10.1093/intimm/dxad011
Wajid Amin, Shoki Nishio, Tasuku Honjo, Maki Kobayashi
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Abstract

Activation-induced cytidine deaminase (AID)-dependent DNA cleavage is the initial event of antibody gene-diversification processes such as class switch recombination (CSR) and somatic hypermutation (SHM). We previously reported the requirement of an AID-dependent decrease of topoisomerase 1 (Top1) for efficient DNA cleavage, but the underlying molecular mechanism has remained elusive. This study focuses on HuR/ELAVL1, a protein that binds to AU-rich elements in RNA. HuR-knockout (KO) CH12 cells derived from murine B lymphoma cells were found to have lower CSR and hypermutation efficiencies due to decreased AID-dependent DNA cleavage levels. The HuR-KO CH12 cells do not show impairment in cell cycles and Myc expression, which have been reported in HuR-reduced spleen B cells. Furthermore, drugs that scavenge reactive oxygen species (ROS) do not rescue the lower CSR in HuR-KO CH12 cells, meaning that ROS or decreased c-Myc protein amount is not the reason for the deficiencies of CSR and hypermutation in HuR-KO CH12 cells. We show that HuR binds to Top1 mRNA and that complete deletion of HuR abolishes AID-dependent repression of Top1 protein synthesis in CH12 cells. Additionally, reduction of CSR to IgG3 in HuR-KO cells is rescued by knockdown of Top1, indicating that elimination of the AID-dependent Top1 decrease is the cause of the inefficiency of DNA cleavage, CSR and hypermutation in HuR-KO cells. These results show that HuR is required for initiation of antibody diversification and acquired immunity through the regulation of AID-dependent DNA cleavage by repressing Top1 protein synthesis.

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HuR/ELAVL1在抗体多样化中激活诱导胞苷脱氨酶依赖性拓扑异构酶1减少的必要性。
激活诱导胞苷脱氨酶(AID)依赖的DNA切割是抗体基因多样化过程的初始事件,如类开关重组(CSR)和体细胞超突变(SHM)。我们之前报道了aids依赖性的拓扑异构酶1 (Top1)的减少对高效DNA切割的要求,但其潜在的分子机制仍然难以捉摸。这项研究的重点是HuR/ELAVL1,一种结合RNA中富含au元素的蛋白质。来自小鼠B淋巴瘤细胞的hhr敲除(KO) CH12细胞被发现具有较低的CSR和高突变效率,这是由于艾滋病依赖性DNA切割水平降低。HuR-KO CH12细胞没有表现出细胞周期和Myc表达的损伤,这在hur减少的脾B细胞中有报道。此外,清除活性氧(ROS)的药物不能挽救hr - ko CH12细胞中较低的CSR,这意味着ROS或c-Myc蛋白量的减少并不是hr - ko CH12细胞中CSR缺乏和高突变的原因。我们发现,在CH12细胞中,HuR与Top1 mRNA结合,完全缺失HuR可消除艾滋病依赖性的Top1蛋白合成抑制。此外,在hr - ko细胞中,CSR减少到IgG3是通过敲低Top1来挽救的,这表明消除艾滋病依赖性的Top1减少是hr - ko细胞中DNA切割效率低下、CSR和高突变的原因。这些结果表明,HuR是通过抑制Top1蛋白合成来调节艾滋病依赖性DNA切割,从而启动抗体多样化和获得性免疫所必需的。
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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
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