AUTHOR=Suwandi Abdulhadi , Menon Manoj B. , Kotlyarov Alexey , Grassl Guntram A. , Gaestel Matthias 

TITLE=p38MAPK/MK2 signaling stimulates host cells autophagy pathways to restrict Salmonella infection

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1245443

DOI=10.3389/fimmu.2023.1245443

ISSN=1664-3224

ABSTRACT=<p>Autophagy plays an important role in recognizing and protecting cells from invading intracellular pathogens such as <italic>Salmonella</italic>. In this work, we investigated the role of p38<sup>MAPK</sup>/MK2 in modulating the host cell susceptibility to <italic>Salmonella</italic> infection. Inhibition of p38<sup>MAPK</sup> or MK2 led to a significant increase of bacterial counts in <italic>Salmonella</italic> infected mouse embryonic fibroblasts (MEFs), as well as in MK2-deficient (<italic>Mk2<sup>-/-</sup></italic>) cells. Furthermore, western blot analysis showed that <italic>Mk2<sup>-/-</sup></italic> cells have lower level of LC3 lipidation, which is the indicator of general autophagy compared to <italic>Mk2</italic>-rescued cells. In <italic>Mk2<sup>-/-</sup></italic> cells, we also observed lower activated TANK-binding kinase-1 phosphorylation on Ser172 and p62/SQTM1-Ser403 phosphorylation, which are important to promote the translocation of p62 to ubiquitinated microbes and required for efficient autophagy of bacteria. Furthermore, immunofluorescence analysis revealed reduced colocalization of <italic>Salmonella</italic> with LC3 and p62 in MEFs. Inhibition of autophagy with bafilomycin A1 showed increased bacterial counts in treated cells compared to control cell. Overall, these results indicate that p38<sup>MAPK</sup>/MK2-mediated protein phosphorylation modulates the host cell susceptibility to <italic>Salmonella</italic> infection by affecting the autophagy pathways.</p>