The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection. (25th October 2022)

• Record Type: Journal Article
• Authors: Bilkei‐Gorzo, Orsolya; Heunis, Tiaan; Marín‐Rubio, José Luis; Cianfanelli, Francesca Romana; Raymond, Benjamin Bernard Armando; Inns, Joseph; Fabrikova, Daniela; Peltier, Julien; Oakley, Fiona; Schmid, Ralf; Härtlova, Anetta; Trost, Matthias
• Is Part Of: EMBO journal. Volume 41:Number 23(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-25
• Subjects: E3 ligase -- macrophage -- phagosome -- RNF115 -- ubiquitin; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021108970
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: Interferon gamma activation of macrophages increases phagocytic uptake of particles, but delays phagosomal maturation via unclear mechanisms. Here, a phagosome‐localised E3 ubiquitin ligase, RNF115, is shown to control phagosomal maturation and cytokine responses to bacterial infection in vitro and in vivo . Quantitative proteomics reveal high levels of typical and atypical ubiquitin chain types on phagosomal proteins. RNF115 is enriched on phagosomes and ubiquitylates various proteins involved in immune responses and vesicle trafficking. RNF115 regulates Salmonella adaptation and replication within macrophages. Loss of RNF115 increases inflammatory responses in vitro and reduces tissue damage to infection in knock‐out mice. Abstract : 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 .