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

Härtlova, A; Herbst, S; Peltier, J; Rodgers, A; Bilkei-Gorzo, O; Fearns, A; Dill, BD; ... Gutierrez, MG; + view all (2018) LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages. The EMBO Journal , 2018 , Article e98694. 10.15252/embj.201798694. (In press). Green open access

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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.

Type: Article
Title: LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.201798694
Publisher version: http://doi.org/10.15252/embj.201798694
Language: English
Additional information: Copyright © 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 Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: LRRK2, Parkinson's disease, Rubicon, phagosome, tuberculosis
URI: http://discovery.ucl.ac.uk/id/eprint/10049910
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