TPL‐2 kinase induces phagosome acidification to promote macrophage killing of bacteria

Breyer, Felix; Härtlová, Anetta; Thurston, Teresa L. M.; Flynn, Helen; Chakravarty, Probir; Janzen, Julia; Peltier, Julien; Heunis, Tiaan; Snijders, Ambrosius P; Trost, Matthias; Ley, Steven C.

doi:10.15252/embj.2020106188

Cited by 19 publications

(9 citation statements)

References 65 publications

(84 reference statements)

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“…Lysosomal hydrolases and antimicrobial activities ( 40, 41 ) require an acidic environment for their functions; the acidic lysosome environment is provided by the activity of a V-ATPase that comprises multiple V0 and V1 protein subunits ( 42 ). Although the mRNA level of V-ATPase subunits did not differ significantly different between infected and bystander cells, RNA-seq revealed lower expression of multiple V-ATPase subunits in MNC1 compared with AM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mycobacterium tuberculosisresides in lysosome-poor monocyte-derived lung cells during chronic infection

Zheng

Chang

Limberis

et al. 2023

Preprint

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Mycobacterium tuberculosis (Mtb) infects multiple lung myeloid cell subsets and causes persistent infection despite innate and adaptive immune responses. However, the mechanisms allowing Mtb to evade elimination are not fully understood. Here, using new methods, we determined that after T cell responses have developed, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb compared to alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Bulk RNA sequencing revealed that the lysosome biogenesis pathway is downregulated in MNC1. Functional assays confirmed that Mtb-permissive MNC1 are deficient in lysosome content, acidification, and proteolytic activity compared to AM, and have less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in MNC1 in vivo. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these cell subsets as a virulence mechanism that requires the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome function of primary macrophages in vitro and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results indicate that Mtb exploits lysosome-poor monocyte-derived cells for in vivo persistence; targeting lysosome biogenesis may be an effective approach to host-directed therapy for tuberculosis, enabling permissive lung cells to restrict and kill Mtb through phagolysosome and autolysosome maturation.

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Section: Resultsmentioning

confidence: 99%

Mycobacterium tuberculosisresides in lysosome-poor monocyte-derived lung cells during chronic infection

Zheng

Chang

Limberis

et al. 2023

Preprint

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“…To further identify components of the ubiquitin system involved in the regulation of phagosome function in IFN‐γ activated macrophages, we analysed the phagosomal proteome of resting and IFN‐γ‐activated macrophages by a quantitative mass spectrometry approach (Dill et al , 2015 ; Hartlova et al , 2018 ; Guo et al , 2019 ; Breyer et al , 2021 ) (Fig 2A , Dataset EV1 ). We identified several proteins of the ubiquitin system, including ubiquitin and ubiquitin‐like modifiers, DUBs, E1 and E2 enzymes (Fig 2B ) as well as E3 ligases (Fig 2C ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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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-c) 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-c activation of macrophages, suggesting a role in regulating phagosomal functions. We identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN-c 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.

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“…To further identify components of the ubiquitin system involved in the regulation of phagosome function in IFN-γ activated macrophages, we analysed the phagosomal proteome of resting and IFN-γ activated macrophages by a quantitative mass spectrometry approach (Breyer et al, 2021, Dill et al, 2015, Guo et al, 2019, Hartlova et al, 2018) (Figure 2A, Supplementary Table 1) . We identified several proteins of the ubiquitin system, including ubiquitin and ubiquitin-like modifiers, DUBs, E1 and E2 enzymes (Figure 2B) as well as E3 ligases (Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

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

Bilkei‐Gorzo

Heunis

Fabrikova

et al. 2021

Preprint

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Phagocytosis as a key process in innate immunity and homeostasis. After uptake, newly formed phagosomes mature by acquisition of endo-lysosomal 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. Furthermore, 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 Staphylococcus aureus, 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.

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TPL‐2 kinase induces phagosome acidification to promote macrophage killing of bacteria

Cited by 19 publications

References 65 publications

Mycobacterium tuberculosisresides in lysosome-poor monocyte-derived lung cells during chronic infection

Mycobacterium tuberculosisresides in lysosome-poor monocyte-derived lung cells during chronic infection

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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