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The EMBO Journal - 2022 - Bilkei‐Gorzo - The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to.pdf (4.01 MB)

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

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posted on 2023-11-06, 12:06 authored by O Bilkei-Gorzo, T Heunis, JL Marín-Rubio, FR Cianfanelli, BBA Raymond, J Inns, D Fabrikova, J Peltier, F Oakley, R Schmid, A Härtlova, M Trost

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.

History

Author affiliation

Leicester Institute of Structural and Chemical Biology, University of Leicester

Version

  • VoR (Version of Record)

Published in

EMBO Journal

Volume

41

Issue

23

Pagination

e108970

Publisher

EMBO

issn

0261-4189

eissn

1460-2075

Copyright date

2022

Available date

2023-11-06

Spatial coverage

England

Language

eng

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