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Lookup NU author(s): Dr Julien Peltier, Professor Matthias TrostORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2018 EMBO. 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.
Author(s): Hartlova 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
Publication type: Article
Publication status: Published
Journal: EMBO Journal
Year: 2018
Volume: 37
Issue: 11
Print publication date: 01/06/2018
Online publication date: 22/05/2018
Acceptance date: 24/04/2018
Date deposited: 12/06/2018
ISSN (print): 0261-4189
ISSN (electronic): 1460-2075
Publisher: Wiley - VCH Verlag
URL: https://doi.org/10.15252/embj.201798694
DOI: 10.15252/embj.201798694
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