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EMBO J. 2018 Jun 15;37(12). pii: e98694. doi: 10.15252/embj.201798694. Epub 2018 May 22.

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

Author information

1
MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
2
Newcastle University, Newcastle-upon-Tyne, UK.
3
Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, UK.
4
Crick-GSK Biomedical LinkLabs, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, UK.
5
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
6
University of Reading, Reading, UK.
7
UCL Institute of Neurology, Queen Square, London, UK.
8
NIEHS, Research Triangle Park, NC, USA.
9
Neurodegeneration Discovery Performance Unit, RD Neurosciences, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, UK.
10
MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK matthias.trost@ncl.ac.uk max.g@crick.ac.uk.
11
Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, UK matthias.trost@ncl.ac.uk max.g@crick.ac.uk.

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

PMID:
29789389
PMCID:
PMC6003659
DOI:
10.15252/embj.201798694
[Indexed for MEDLINE]
Free PMC Article

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