The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection.
The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection.
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DOI：
10.15252/embj.2021108970
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发表时间：
2022-12-01
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吞噬作用是先天免疫和动态平衡的关键过程。在颗粒摄取后，新形成的吞噬小体通过获得内溶酶体酶而成熟。干扰素-γ激活巨噬细胞可增强杀菌活性，但以未知机制延缓吞噬小体成熟。利用定量蛋白质组学，我们发现吞噬体蛋白含有高水平的典型和非典型泛素链类型。此外，吞噬体泛素化的囊泡运输蛋白在巨噬细胞的干扰素-γ激活后显著增强，这表明吞噬体有调节吞噬功能的作用。我们发现E3泛素连接酶RNF115是巨噬细胞吞噬小体成熟的重要调节因子，它富含在干扰素-γ激活的巨噬细胞的吞噬小体上。RNF115蛋白或连接酶活性的丧失促进了吞噬小体的成熟，并增加了对细菌感染的细胞因子反应，表明吞噬小体的先天免疫信号和吞噬小体的运输都是通过泛素化来控制的。RNF115基因敲除小鼠对金黄色葡萄球菌感染的组织损伤较小，表明RNF115在体内炎症反应中发挥作用。总之，RNF115和吞噬体泛素化是细菌感染过程中天然免疫功能的重要调节因子。一种富含吞噬小体的E3连接酶泛素化免疫反应和囊泡运输蛋白，并控制分离的巨噬细胞内的细菌复制以及体内的炎症。
Phagocytosis is a key process in innate immunity and homeostasis. After particle uptake, newly formed phagosomes mature by acquisition of endolysosomal enzymes. Macrophage activation by interferon gamma (IFN‐γ) increases microbicidal activity, but delays phagosomal maturation by an unknown mechanism. Using quantitative proteomics, we show that phagosomal proteins harbour high levels of typical and atypical ubiquitin chain types. Moreover, phagosomal ubiquitylation of vesicle trafficking proteins is substantially enhanced upon IFN‐γ activation of macrophages, suggesting a role in regulating phagosomal functions. We identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN‐γ activated macrophages, as an important regulator of phagosomal maturation. Loss of RNF115 protein or ligase activity enhanced phagosomal maturation and increased cytokine responses to bacterial infection, suggesting that both innate immune signalling from the phagosome and phagolysosomal trafficking are controlled through ubiquitylation. RNF115 knock‐out mice show less tissue damage in response to S. aureus infection, indicating a role of RNF115 in inflammatory responses in vivo. In conclusion, RNF115 and phagosomal ubiquitylation are important regulators of innate immune functions during bacterial infections. A phagosome‐enriched E3 ligase ubiquitylates immune response and vesicle trafficking proteins, and controls bacterial replication within isolated macrophages as well as inflammation in vivo.