Nemo介导的基因表达变化对DNA双链断裂的响应离不开依赖ATM的Nemo SQ位点磷酸化。

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Rebecca A Glynn, Katharina E Hayer, Craig H Bassing
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引用次数: 0

摘要

在对 DNA 双链断裂(DSB)做出反应时,ATM 激酶会激活 NF-κB 因子,刺激基因表达发生变化,从而促进存活并为细胞修复损伤留出时间。在细胞系中,ATM 可通过两种独立、趋同的机制激活 NF-κB 转录因子。一种是 ATM 介导的核 NF-κB 重要调节因子(Nemo)蛋白磷酸化,导致 Nemo 单泛素化并输出到细胞质,在细胞质中与 IκB 激酶(IKK)复合物结合激活 NF-κB。另一种情况是,DSB 触发 ATM 迁移到细胞质中,在那里促进 Nemo 的单泛素化,并导致 IKK 介导的 NF-κB 激活。除了激活 NF-κB 之外,ATM 在 DSB 反应中还有许多其他功能,而 Nemo 会在各种刺激(包括发育或促炎刺激,如 LPSs)的下游激活 NF-κB。为了阐明DSB诱导的、依赖于ATM的NF-κB反应基因表达变化在体内的作用,我们培育了表达磷酸突变Nemo蛋白的小鼠,这些小鼠缺乏ATM或相关激酶磷酸化的共识SQ位点。我们证明,这些小鼠存活/健康、能育,并表现出整体正常的 B 淋巴细胞和 T 淋巴细胞发育。此外,用 LPS 处理这些小鼠的 B 系细胞可诱导正常的 NF-κB 调节基因表达变化。此外,与前 B 细胞系的结果明显不同的是,表达磷酸突变体 Nemo 的原代 B 系细胞经基因毒性药物依托泊苷处理后,NF-κB 调控基因的表达会发生正常的 ATM 和 Nemo 依赖性变化。我们的数据证明,体内 Nemo SQ 键依赖于 ATM 的磷酸化在 DSB 信号的 NF-κB 调节基因表达变化中是不可或缺的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ATM-dependent Phosphorylation of Nemo SQ Motifs Is Dispensable for Nemo-mediated Gene Expression Changes in Response to DNA Double-Strand Breaks.

In response to DNA double-strand breaks (DSBs), the ATM kinase activates NF-κB factors to stimulate gene expression changes that promote survival and allow time for cells to repair damage. In cell lines, ATM can activate NF-κB transcription factors via two independent, convergent mechanisms. One is ATM-mediated phosphorylation of nuclear NF-κB essential modulator (Nemo) protein, which leads to monoubiquitylation and export of Nemo to the cytoplasm where it engages the IκB kinase (IKK) complex to activate NF-κB. Another is DSB-triggered migration of ATM into the cytoplasm, where it promotes monoubiquitylation of Nemo and the resulting IKK-mediated activation of NF-κB. ATM has many other functions in the DSB response beyond activation of NF-κB, and Nemo activates NF-κB downstream of diverse stimuli, including developmental or proinflammatory stimuli such as LPSs. To elucidate the in vivo role of DSB-induced, ATM-dependent changes in expression of NF-κB-responsive genes, we generated mice expressing phosphomutant Nemo protein lacking consensus SQ sites for phosphorylation by ATM or related kinases. We demonstrate that these mice are viable/healthy and fertile and exhibit overall normal B and T lymphocyte development. Moreover, treatment of their B lineage cells with LPS induces normal NF-κB-regulated gene expression changes. Furthermore, in marked contrast to results from a pre-B cell line, primary B lineage cells expressing phosphomutant Nemo treated with the genotoxic drug etoposide induce normal ATM- and Nemo-dependent changes in expression of NF-κB-regulated genes. Our data demonstrate that ATM-dependent phosphorylation of Nemo SQ motifs in vivo is dispensable for DSB-signaled changes in expression of NF-κB-regulated genes.

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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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