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

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Title: TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria
Authors: Breyer, F
Hartlova, A
Thurston, T
Flynn, HR
Chakravarty, P
Janzen, J
Peltier, J
Heunis, T
Snijders, AP
Trost, M
Ley, SC
Item Type: Journal Article
Abstract: Tumour progression locus 2 (TPL-2) kinase mediates Toll-like receptor (TLR) activation of ERK1/2 and p38α MAP kinases in myeloid cells to modulate expression of key cytokines in innate immunity. This study identified a novel MAP kinase-independent regulatory function for TPL-2 in phagosome maturation, an essential process for killing of phagocytosed microbes. TPL-2 catalytic activity was demonstrated to induce phagosome acidification and proteolysis in primary mouse and human macrophages following uptake of latex beads. Quantitative proteomics revealed that blocking TPL-2 catalytic activity significantly altered the protein composition of phagosomes, particularly reducing the abundance of V-ATPase proton pump subunits. Furthermore, TPL-2 stimulated the phosphorylation of DMXL1, a regulator of V-ATPases, to induce V-ATPase assembly and phagosome acidification. Consistent with these results, TPL-2 catalytic activity was required for phagosome acidification and the efficient killing of Staphylococcus aureus and Citrobacter rodentium following phagocytic uptake by macrophages. TPL-2 therefore controls innate immune responses of macrophages to bacteria via V-ATPase induction of phagosome maturation.
Issue Date: 21-Apr-2021
Date of Acceptance: 15-Mar-2021
URI: http://hdl.handle.net/10044/1/89134
DOI: 10.15252/embj.2020106188
ISSN: 0261-4189
Publisher: EMBO Press
Start Page: 1
End Page: 19
Journal / Book Title: The EMBO Journal
Volume: 40
Copyright Statement: ª 2021 The Authors. Published under the terms of the CC BY 4.0 license
Sponsor/Funder: The Francis Crick Institute Limited
Funder's Grant Number: CR2018/002CH; PO60157091
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
DMXL1
macrophage phagosome
Staphylococcus aureus
TPL&#8208
2 kinase
V&#8208
ATPase
Staphylococcus aureus
DMXL1
TPL-2 kinase
V-ATPase
macrophage phagosome
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
DMXL1
macrophage phagosome
Staphylococcus aureus
TPL&#8208
2 kinase
V&#8208
ATPase
06 Biological Sciences
08 Information and Computing Sciences
11 Medical and Health Sciences
Developmental Biology
Publication Status: Published
Article Number: ARTN e106188
Online Publication Date: 2021-04-21
Appears in Collections:Department of Immunology and Inflammation
Department of Infectious Diseases



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