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

Lookup NU author(s): Dr Julien Peltier, Dr Tiaan Heunis, Professor Matthias TrostORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2021 The Authors. Published under the terms of the CC BY 4.0 licenseTumour 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.

Publication metadata

Author(s): Breyer F, Hartlova A, Thurston T, Flynn HR, Chakravarty P, Janzen J, Peltier J, Heunis T, Snijders AP, Trost M, Ley SC

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2021

Online publication date: 21/04/2021

Acceptance date: 15/03/2021

Date deposited: 13/05/2021

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.15252/embj.2020106188

DOI: 10.15252/embj.2020106188

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