Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5

Andrew S. Gilbert, Paula I. Seoane, Poppy Sephton-Clark, Aleksandra Bojarczuk, Richard Hotham, Emanuele Giurisato, Adil R. Sarhan, Amy Hillen, Greetje Vande Velde, Nathanael S. Gray, Dario R. Alessi, Debbie L. Cunningham, Cathy Tournier, Simon A. Johnston, Robin C. May (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)
127 Downloads (Pure)

Abstract

Vomocytosis, or nonlytic extrusion, is a poorly understood process through which macrophages release live pathogens that they have failed to kill back into the extracellular environment. Vomocytosis is conserved across vertebrates and occurs with a diverse range of pathogens, but to date, the host signaling events that underpin expulsion remain entirely unknown. We use a targeted inhibitor screen to identify the MAP kinase ERK5 as a critical suppressor of vomocytosis. Pharmacological inhibition or genetic manipulation of ERK5 activity significantly raises vomocytosis rates in human macrophages, whereas stimulation of the ERK5 signaling pathway inhibits vomocytosis. Lastly, using a zebrafish model of cryptococcal disease, we show that reducing ERK5 activity in vivo stimulates vomocytosis and results in reduced dissemination of infection. ERK5 therefore represents the first host signaling regulator of vomocytosis to be identified and a potential target for the future development of vomocytosis-modulating therapies.

Original languageEnglish
Article numbere1700898
Pages (from-to)1-9
Number of pages9
JournalScience Advances
Volume3
Issue number8
DOIs
Publication statusPublished - 16 Aug 2017

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