Scribble 与 NADPH 氧化酶复合物之间的相互作用控制 M1 巨噬细胞的极化和功能。
An interaction between Scribble and the NADPH oxidase complex controls M1 macrophage polarization and function.
机构信息
Princess Margaret Cancer Center and Department of Medical Biophysics, University of Toronto, Toronto M5G 2M9, Canada.
Cancer Research Institute, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts 02115, USA.
出版信息
Nat Cell Biol. 2016 Nov;18(11):1244-1252. doi: 10.1038/ncb3413. Epub 2016 Oct 3.
The polarity protein Scribble (SCRIB) regulates apical-basal polarity, directional migration and tumour suppression in Drosophila and mammals. Here we report that SCRIB is an important regulator of myeloid cell functions including bacterial infection and inflammation. SCRIB interacts directly with the NADPH oxidase (NOX) complex in a PSD95/Dlg/ZO-1 (PDZ)-domain-dependent manner and is required for NOX-induced reactive oxygen species (ROS) generation in culture and in vivo. On bacterial infection, SCRIB localized to phagosomes in a leucine-rich repeat-dependent manner and promoted ROS production within phagosomes to kill bacteria. Unexpectedly, SCRIB loss promoted M1 macrophage polarization and inflammation. Thus, SCRIB uncouples ROS-dependent bacterial killing activity from M1 polarization and inflammatory functions of macrophages. Modulating the SCRIB-NOX pathway can therefore identify ways to manage infection and inflammation with implications for chronic inflammatory diseases, sepsis and cancer.
极性蛋白 Scribble（SCRIB）在果蝇和哺乳动物中调节顶端-基底极性、定向迁移和肿瘤抑制。在这里，我们报告 SCRIB 是髓样细胞功能的重要调节剂，包括细菌感染和炎症。SCRIB 以 PSD95/Dlg/ZO-1（PDZ）结构域依赖性的方式直接与 NADPH 氧化酶（NOX）复合物相互作用，并且在培养物和体内均需要 NOX 诱导的活性氧（ROS）生成。在细菌感染时，SCRIB 以亮氨酸丰富重复（LRR）依赖性的方式定位于吞噬体，并促进吞噬体内的 ROS 生成以杀死细菌。出乎意料的是，SCRIB 的缺失促进了 M1 巨噬细胞极化和炎症。因此，SCRIB 将 ROS 依赖性的杀菌活性与巨噬细胞的 M1 极化和炎症功能分离。因此，调节 SCRIB-NOX 途径可以确定管理感染和炎症的方法，这对慢性炎症性疾病、败血症和癌症具有重要意义。
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