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

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 u...

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Autores principales: Härtlova, Anetta, Herbst, Susanne, Peltier, Julien, Rodgers, Angela, Bilkei‐Gorzo, Orsolya, Fearns, Antony, Dill, Brian D, Lee, Heyne, Flynn, Rowan, Cowley, Sally A, Davies, Paul, Lewis, Patrick A, Ganley, Ian G, Martinez, Jennifer, Alessi, Dario R, Reith, Alastair D, Trost, Matthias, Gutierrez, Maximiliano G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003659/
https://www.ncbi.nlm.nih.gov/pubmed/29789389
http://dx.doi.org/10.15252/embj.201798694
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author Härtlova, Anetta
Herbst, Susanne
Peltier, Julien
Rodgers, Angela
Bilkei‐Gorzo, Orsolya
Fearns, Antony
Dill, Brian D
Lee, Heyne
Flynn, Rowan
Cowley, Sally A
Davies, Paul
Lewis, Patrick A
Ganley, Ian G
Martinez, Jennifer
Alessi, Dario R
Reith, Alastair D
Trost, Matthias
Gutierrez, Maximiliano G
author_facet Härtlova, Anetta
Herbst, Susanne
Peltier, Julien
Rodgers, Angela
Bilkei‐Gorzo, Orsolya
Fearns, Antony
Dill, Brian D
Lee, Heyne
Flynn, Rowan
Cowley, Sally A
Davies, Paul
Lewis, Patrick A
Ganley, Ian G
Martinez, Jennifer
Alessi, Dario R
Reith, Alastair D
Trost, Matthias
Gutierrez, Maximiliano G
author_sort Härtlova, Anetta
collection PubMed
description 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.
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spelling pubmed-60036592018-06-26 LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages Härtlova, Anetta Herbst, Susanne Peltier, Julien Rodgers, Angela Bilkei‐Gorzo, Orsolya Fearns, Antony Dill, Brian D Lee, Heyne Flynn, Rowan Cowley, Sally A Davies, Paul Lewis, Patrick A Ganley, Ian G Martinez, Jennifer Alessi, Dario R Reith, Alastair D Trost, Matthias Gutierrez, Maximiliano G EMBO J Articles 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. John Wiley and Sons Inc. 2018-05-22 2018-06-15 /pmc/articles/PMC6003659/ /pubmed/29789389 http://dx.doi.org/10.15252/embj.201798694 Text en © 2018 The Francis Crick Institute. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Härtlova, Anetta
Herbst, Susanne
Peltier, Julien
Rodgers, Angela
Bilkei‐Gorzo, Orsolya
Fearns, Antony
Dill, Brian D
Lee, Heyne
Flynn, Rowan
Cowley, Sally A
Davies, Paul
Lewis, Patrick A
Ganley, Ian G
Martinez, Jennifer
Alessi, Dario R
Reith, Alastair D
Trost, Matthias
Gutierrez, Maximiliano G
LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
title LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
title_full LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
title_fullStr LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
title_full_unstemmed LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
title_short LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
title_sort lrrk2 is a negative regulator of mycobacterium tuberculosis phagosome maturation in macrophages
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003659/
https://www.ncbi.nlm.nih.gov/pubmed/29789389
http://dx.doi.org/10.15252/embj.201798694
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