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

doi:10.1126/sciadv.1700898

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)

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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 language	English
Article number	e1700898
Pages (from-to)	1-9
Number of pages	9
Journal	Science Advances
Volume	3
Issue number	8
DOIs	https://doi.org/10.1126/sciadv.1700898
Publication status	Published - 16 Aug 2017

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© 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
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Gilbert, A. S., Seoane, P. I., Sephton-Clark, P., Bojarczuk, A., Hotham, R., Giurisato, E., Sarhan, A. R., Hillen, A., Velde, G. V., Gray, N. S., Alessi, D. R., Cunningham, D. L., Tournier, C., Johnston, S. A., & May, R. C. (2017). Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5. Science Advances, 3(8), 1-9. Article e1700898. https://doi.org/10.1126/sciadv.1700898

@article{fd9dbe2794c046ed88dbe66da9a63b6e,

title = "Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5",

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.",

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

note = "A.S.G., P.I.S., and R.C.M. are supported by project MitoFun, funded by the European Research Council under the European Union{\textquoteright}s Seventh Framework Programme (FP/2007-2013)/ERC grant agreement no. 614562 and by a Wolfson Research Merit Award from the Royal Society (to R.C.M.), a Biotechnology and Biological Sciences Research Council Midlands Integrative Biosciences Training Partnership Studentship (to A.S.G.), and a scholarship from the Darwin Trust of Edinburgh (to P.I.S.). S.A.J. and A.B. were supported by Medical Research Council and Department for International Development Career Development Award Fellowship (MR/J009156/1). S.A.J. was additionally supported by a Krebs Institute Fellowship, the Medical Research Foundation (grant R/140419), and the Medical Research Council Center (grant G0700091). R.H. was supported by a Colin Beattie Biomedical Science scholarship. A.R.S. was supported by a scholarship from the Higher Committee for Education Development in Iraq. E.G. was supported by a Marie Curie Research Fellowship, and C.T. is supported by a grant from Worldwide Cancer Research. G.V.V. is supportedby a postdoctoral grant from the Flemish Research Foundation. D.R.A. acknowledges funding from the UK Medical Research Council (grant number MC-UU_1201612).",

year = "2017",

month = aug,

day = "16",

doi = "10.1126/sciadv.1700898",

language = "English",

volume = "3",

pages = "1--9",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "8",

}

Gilbert, AS, Seoane, PI, Sephton-Clark, P, Bojarczuk, A, Hotham, R, Giurisato, E, Sarhan, AR, Hillen, A, Velde, GV, Gray, NS, Alessi, DR, Cunningham, DL, Tournier, C, Johnston, SA & May, RC 2017, 'Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5', Science Advances, vol. 3, no. 8, e1700898, pp. 1-9. https://doi.org/10.1126/sciadv.1700898

TY - JOUR

T1 - Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5

AU - Gilbert, Andrew S.

AU - Seoane, Paula I.

AU - Sephton-Clark, Poppy

AU - Bojarczuk, Aleksandra

AU - Hotham, Richard

AU - Giurisato, Emanuele

AU - Sarhan, Adil R.

AU - Hillen, Amy

AU - Velde, Greetje Vande

AU - Gray, Nathanael S.

AU - Alessi, Dario R.

AU - Cunningham, Debbie L.

AU - Tournier, Cathy

AU - Johnston, Simon A.

AU - May, Robin C.

N1 - A.S.G., P.I.S., and R.C.M. are supported by project MitoFun, funded by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC grant agreement no. 614562 and by a Wolfson Research Merit Award from the Royal Society (to R.C.M.), a Biotechnology and Biological Sciences Research Council Midlands Integrative Biosciences Training Partnership Studentship (to A.S.G.), and a scholarship from the Darwin Trust of Edinburgh (to P.I.S.). S.A.J. and A.B. were supported by Medical Research Council and Department for International Development Career Development Award Fellowship (MR/J009156/1). S.A.J. was additionally supported by a Krebs Institute Fellowship, the Medical Research Foundation (grant R/140419), and the Medical Research Council Center (grant G0700091). R.H. was supported by a Colin Beattie Biomedical Science scholarship. A.R.S. was supported by a scholarship from the Higher Committee for Education Development in Iraq. E.G. was supported by a Marie Curie Research Fellowship, and C.T. is supported by a grant from Worldwide Cancer Research. G.V.V. is supportedby a postdoctoral grant from the Flemish Research Foundation. D.R.A. acknowledges funding from the UK Medical Research Council (grant number MC-UU_1201612).

PY - 2017/8/16

Y1 - 2017/8/16

N2 - 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.

AB - 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.

U2 - 10.1126/sciadv.1700898

DO - 10.1126/sciadv.1700898

M3 - Article

C2 - 28835924

SN - 2375-2548

VL - 3

SP - 1

EP - 9

JO - Science Advances

JF - Science Advances

IS - 8

M1 - e1700898

ER -

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

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