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

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Phagocytosis is crucial for innate immunity and cellular homeostasis.
• Macrophages, activated by interferon gamma (IFN-γ), exhibit enhanced microbicidal activity but delayed phagosomal maturation.
• The precise mechanism behind IFN-γ-induced delay in phagosomal maturation remains unclear.

Purpose of the Study:

• To investigate the role of ubiquitylation in regulating phagosomal maturation during macrophage activation.
• To identify specific ubiquitin ligases involved in this process.
• To elucidate the function of RNF115 in innate immune responses to bacterial infection.

Main Methods:

• Quantitative proteomics was employed to analyze phagosomal protein ubiquitylation.
• Macrophage activation with IFN-γ was performed to study changes in ubiquitylation patterns.
• RNF115 function was assessed through protein depletion and ligase activity assays.
• RNF115 knockout mice were used to evaluate in vivo inflammatory responses.

Main Results:

• Phagosomal proteins exhibit diverse ubiquitin chain types, with enhanced ubiquitylation of vesicle trafficking proteins upon IFN-γ activation.
• The E3 ubiquitin ligase RNF115 was identified as being enriched on phagosomes of IFN-γ activated macrophages.
• Loss of RNF115 accelerated phagosomal maturation and boosted cytokine responses to bacterial infection.
• RNF115 knockout mice demonstrated reduced tissue damage following Staphylococcus aureus infection.

Conclusions:

• Phagosomal ubiquitylation, regulated by RNF115, is a key mechanism controlling phagosomal maturation and innate immune signaling.
• RNF115 plays a significant role in modulating inflammatory responses and tissue damage during bacterial infections in vivo.
• Targeting RNF115-mediated ubiquitylation pathways may offer therapeutic strategies for bacterial infections.