The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection

• DOI: 10.15252/embj.2021108970
• Publication Date: 2022-10-25T07:26:32Z
• Authors: Orsolya Bilkei‐Gorzo; Tiaan Heunis; José Luis Marín‐R...; Francesca Romana ...; Benjamin Bernard ...; Joseph Inns; Daniela Fabrikova; Julien Peltier; Fiona Oakley; Ralf Schmid; Anetta Härtlova; Matthias Trost
• Keywords: 0301 basic medicine; Staphylococcus aureus; 0303 health sciences; Ubiquitin-Protein Ligases; Articles; Bacterial Infections; 3. Good health; Mice; Interferon-gamma; 03 medical and health sciences; Phagocytosis; Phagosomes; Animals

AbstractPhagocytosis 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.