Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst.
Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst.
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DOI：
10.1038/ncomms8838
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发表时间：
2015-07-21
影响因子：
16.6
通讯作者：
Xavier RJ
中科院分区：
文献类型：
--
作者：
Graham DB;Becker CE;Doan A;Goel G;Villablanca EJ;Knights D;Mok A;Ng ACY;Doench JG;Root DE;Clish CB;Xavier RJ
由 Nox2 NADPH 氧化酶衍生的活性氧介导的吞噬细胞氧化爆发，赋予宿主针对多种细菌和真菌病原体的防御能力。损害 Nox2 复合物功能的功能缺失突变会导致危及生命的免疫缺陷，而 Nox2 亚基的遗传变异与炎症性肠病 (IBD) 的发病机制有关。因此，氧化爆发的改变可以深刻影响宿主防御，但人们对微调这种反应的调节机制知之甚少。在此，我们报告通过对与人类炎症性疾病相关的基因座内的基因进行功能筛选，发现了控制氧化爆发的调节节点。通过实施多组学方法，我们定义了分别由 Rbpj、Pfkl 和 Rnf145 控制的转录、代谢和泛素循环节点。此外，我们发现 Rnf145 通过内质网相关降解参与 Nox2 复合物的蛋白质稳态。因此，小鼠巨噬细胞中 Rnf145 的消融增强了细菌清除率，并挽救了与 Ncf4 单倍体不足相关的氧化爆发缺陷。 吞噬细胞采用多种杀菌机制来杀死微生物，包括产生有毒的超氧化物和其他活性氧。在这里，作者利用多组学方法来识别和表征与控制吞噬细胞氧化爆发的粘膜免疫有关的新调节节点。
The phagocyte oxidative burst, mediated by Nox2 NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens. Loss-of-function mutations that impair function of the Nox2 complex result in a life-threatening immunodeficiency, and genetic variants of Nox2 subunits have been implicated in pathogenesis of inflammatory bowel disease (IBD). Thus, alterations in the oxidative burst can profoundly impact host defense, yet little is known about regulatory mechanisms that fine-tune this response. Here we report the discovery of regulatory nodes controlling oxidative burst by functional screening of genes within loci linked to human inflammatory disease. Implementing a multi-omics approach, we define transcriptional, metabolic and ubiquitin-cycling nodes controlled by Rbpj, Pfkl and Rnf145, respectively. Furthermore, we implicate Rnf145 in proteostasis of the Nox2 complex by endoplasmic reticulum-associated degradation. Consequently, ablation of Rnf145 in murine macrophages enhances bacterial clearance, and rescues the oxidative burst defects associated with Ncf4 haploinsufficiency. Phagocytes employ multiple bactericidal mechanisms to kill microorganisms, including the generation of toxic superoxide and other reactive oxygen species. Here the authors utilize a multi-omics approach to identify and characterize new regulatory nodes implicated in mucosal immunity that control phagocyte oxidative burst.