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

More about Open Access at the Crick

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.

Journal details

Pages Epub ahead of print
Available online
Publication date

Crick labs/facilities

Media & press

Media office

Our media office helps journalists interested in Crick research and provides media support to our scientists.

Press resources

Crick logo: go to our image library to download our logo

Additional image resources will be added to this folder shortly.

 

press@crick.ac.uk
 

 

+44 (0)20 3796 5252
 

 

 +44 (0)7918 166 173
(Out of hours number)

 

6 Media crews covering the visit of the King and Queen of Spain, July 2017. Contact our media and press team. Banner image, press at the spanish state visit On Off Off
Acknowledged team