LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages

Anetta Härtlova; Susanne Herbst; Julien Peltier; Angela Rodgers; Orsolya Bilkei-Gorzo; Antony Fearns; Brian D. Dill; Heyne Lee; Rowan Flynn; Sally A. Cowley; Paul Davies; Patrick A. Lewis; Ian G. Ganley; Jennifer Martinez; Dario R. Alessi; Alastair D. Reith; Matthias Trost; Maximiliano G. Gutierrez

doi:10.15252/embj.201798694

LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages

Anetta Härtlova, Susanne Herbst, Julien Peltier, Angela Rodgers, Orsolya Bilkei-Gorzo, Antony Fearns, Brian D. Dill, Heyne Lee, Rowan Flynn, Sally A. Cowley, Paul Davies, Patrick A. Lewis, Ian G. Ganley, Jennifer Martinez, Dario R. Alessi, Alastair D. Reith, Matthias Trost (Lead / Corresponding author), Maximiliano G. Gutierrez (Lead / Corresponding author)

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Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, chronic inflammation and mycobacterial infections. Although there is evidence supporting the idea that LRRK2 has an immune function, the cellular function of this kinase is still largely unknown. By using genetic, pharmacological and proteomics approaches, we show that LRRK2 kinase activity negatively regulates phagosome maturation via the recruitment of the Class III phosphatidylinositol-3 kinase complex and Rubicon to the phagosome in macrophages. Moreover, inhibition of LRRK2 kinase activity in mouse and human macrophages enhanced Mycobacterium tuberculosis phagosome maturation and mycobacterial control independently of autophagy. In vivo, LRRK2 deficiency in mice resulted in a significant decrease in M. tuberculosis burdens early during the infection. Collectively, our findings provide a molecular mechanism explaining genetic evidence linking LRRK2 to mycobacterial diseases and establish an LRRK2-dependent cellular pathway that controls M. tuberculosis replication by regulating phagosome maturation.

Original language	English
Article number	e98694
Number of pages	17
Journal	The EMBO Journal
Volume	37
Issue number	12
Early online date	22 May 2018
DOIs	https://doi.org/10.15252/embj.201798694
Publication status	Published - 15 Jun 2018

Keywords

LRRK2
Parkinson's disease
Rubicon
phagosome
tuberculosis

ASJC Scopus subject areas

Neuroscience(all)
Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.15252/embj.201798694Licence: CC BY

Final Published VersionFinal published version, 1.62 MBLicence: CC BY

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Härtlova, A., Herbst, S., Peltier, J., Rodgers, A., Bilkei-Gorzo, O., Fearns, A., Dill, B. D., Lee, H., Flynn, R., Cowley, S. A., Davies, P., Lewis, P. A., Ganley, I. G., Martinez, J., Alessi, D. R., Reith, A. D., Trost, M., & Gutierrez, M. G. (2018). LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages. The EMBO Journal, 37(12), Article e98694. Advance online publication. https://doi.org/10.15252/embj.201798694

@article{04a2e5c463ca40549d21dc74bdd22f0e,

title = "LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages",

abstract = "Mutations in the leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, chronic inflammation and mycobacterial infections. Although there is evidence supporting the idea that LRRK2 has an immune function, the cellular function of this kinase is still largely unknown. By using genetic, pharmacological and proteomics approaches, we show that LRRK2 kinase activity negatively regulates phagosome maturation via the recruitment of the Class III phosphatidylinositol-3 kinase complex and Rubicon to the phagosome in macrophages. Moreover, inhibition of LRRK2 kinase activity in mouse and human macrophages enhanced Mycobacterium tuberculosis phagosome maturation and mycobacterial control independently of autophagy. In vivo, LRRK2 deficiency in mice resulted in a significant decrease in M. tuberculosis burdens early during the infection. Collectively, our findings provide a molecular mechanism explaining genetic evidence linking LRRK2 to mycobacterial diseases and establish an LRRK2-dependent cellular pathway that controls M. tuberculosis replication by regulating phagosome maturation.",

keywords = "LRRK2, Parkinson's disease, Rubicon, phagosome, tuberculosis",

author = "Anetta H{\"a}rtlova and Susanne Herbst and Julien Peltier and Angela Rodgers and Orsolya Bilkei-Gorzo and Antony Fearns and Dill, {Brian D.} and Heyne Lee and Rowan Flynn and Cowley, {Sally A.} and Paul Davies and Lewis, {Patrick A.} and Ganley, {Ian G.} and Jennifer Martinez and Alessi, {Dario R.} and Reith, {Alastair D.} and Matthias Trost and Gutierrez, {Maximiliano G.}",

note = "This work was funded by Medical Research Council UK (MR/N026004/1 and MR/L010933/1 to PAL, MC_UU_12016/5 to MT and MC_UP_1202/11 to MGG); the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (Boehringer Ingelheim, GSK and Merck KGaA, to MT); the Michael J. Fox Foundation (to MGG and PAL), Parkinson{\textquoteright}s UK Fellowship F1002 to PAL and the Francis Crick Institute (to MGG), which receives its core funding from Cancer Research UK (FC001092), the Medical Research Council UK (FC001092) and the Wellcome Trust (FC001092); the Oxford Martin School (LC0910-004) and the Wellcome Trust (WTISSF121302) to SAC; the Innovative Medicines Initiative Joint Undertaking (IMI JU, 115439), the European Union{\textquoteright}s Seventh Framework Programme, EFPIA companies{\textquoteright} in kind contribution to SAC",

year = "2018",

month = jun,

day = "15",

doi = "10.15252/embj.201798694",

language = "English",

volume = "37",

journal = "The EMBO Journal",

issn = "0261-4189",

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number = "12",

}

Härtlova, A, Herbst, S, Peltier, J, Rodgers, A, Bilkei-Gorzo, O, Fearns, A, Dill, BD, Lee, H, Flynn, R, Cowley, SA, Davies, P, Lewis, PA, Ganley, IG, Martinez, J, Alessi, DR, Reith, AD, Trost, M & Gutierrez, MG 2018, 'LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages', The EMBO Journal, vol. 37, no. 12, e98694. https://doi.org/10.15252/embj.201798694

TY - JOUR

T1 - LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages

AU - Härtlova, Anetta

AU - Herbst, Susanne

AU - Peltier, Julien

AU - Rodgers, Angela

AU - Bilkei-Gorzo, Orsolya

AU - Fearns, Antony

AU - Dill, Brian D.

AU - Lee, Heyne

AU - Flynn, Rowan

AU - Cowley, Sally A.

AU - Davies, Paul

AU - Lewis, Patrick A.

AU - Ganley, Ian G.

AU - Martinez, Jennifer

AU - Alessi, Dario R.

AU - Reith, Alastair D.

AU - Trost, Matthias

AU - Gutierrez, Maximiliano G.

N1 - This work was funded by Medical Research Council UK (MR/N026004/1 and MR/L010933/1 to PAL, MC_UU_12016/5 to MT and MC_UP_1202/11 to MGG); the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (Boehringer Ingelheim, GSK and Merck KGaA, to MT); the Michael J. Fox Foundation (to MGG and PAL), Parkinson’s UK Fellowship F1002 to PAL and the Francis Crick Institute (to MGG), which receives its core funding from Cancer Research UK (FC001092), the Medical Research Council UK (FC001092) and the Wellcome Trust (FC001092); the Oxford Martin School (LC0910-004) and the Wellcome Trust (WTISSF121302) to SAC; the Innovative Medicines Initiative Joint Undertaking (IMI JU, 115439), the European Union’s Seventh Framework Programme, EFPIA companies’ in kind contribution to SAC

PY - 2018/6/15

Y1 - 2018/6/15

N2 - Mutations in the leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, chronic inflammation and mycobacterial infections. Although there is evidence supporting the idea that LRRK2 has an immune function, the cellular function of this kinase is still largely unknown. By using genetic, pharmacological and proteomics approaches, we show that LRRK2 kinase activity negatively regulates phagosome maturation via the recruitment of the Class III phosphatidylinositol-3 kinase complex and Rubicon to the phagosome in macrophages. Moreover, inhibition of LRRK2 kinase activity in mouse and human macrophages enhanced Mycobacterium tuberculosis phagosome maturation and mycobacterial control independently of autophagy. In vivo, LRRK2 deficiency in mice resulted in a significant decrease in M. tuberculosis burdens early during the infection. Collectively, our findings provide a molecular mechanism explaining genetic evidence linking LRRK2 to mycobacterial diseases and establish an LRRK2-dependent cellular pathway that controls M. tuberculosis replication by regulating phagosome maturation.

AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, chronic inflammation and mycobacterial infections. Although there is evidence supporting the idea that LRRK2 has an immune function, the cellular function of this kinase is still largely unknown. By using genetic, pharmacological and proteomics approaches, we show that LRRK2 kinase activity negatively regulates phagosome maturation via the recruitment of the Class III phosphatidylinositol-3 kinase complex and Rubicon to the phagosome in macrophages. Moreover, inhibition of LRRK2 kinase activity in mouse and human macrophages enhanced Mycobacterium tuberculosis phagosome maturation and mycobacterial control independently of autophagy. In vivo, LRRK2 deficiency in mice resulted in a significant decrease in M. tuberculosis burdens early during the infection. Collectively, our findings provide a molecular mechanism explaining genetic evidence linking LRRK2 to mycobacterial diseases and establish an LRRK2-dependent cellular pathway that controls M. tuberculosis replication by regulating phagosome maturation.

KW - LRRK2

KW - Parkinson's disease

KW - Rubicon

KW - phagosome

KW - tuberculosis

U2 - 10.15252/embj.201798694

DO - 10.15252/embj.201798694

M3 - Article

C2 - 29789389

SN - 0261-4189

VL - 37

JO - The EMBO Journal

JF - The EMBO Journal

IS - 12

M1 - e98694

ER -

LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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