LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages |
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| Authors: | 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 |
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| Affiliation: | 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. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK;5. University of Reading, Reading, UK;6. UCL Institute of Neurology, Queen Square, London, UK;7. NIEHS, Research Triangle Park, NC, USA;8. Neurodegeneration Discovery Performance Unit, RD Neurosciences, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, UK |
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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. |
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| Keywords: | LRRK2 Parkinson's disease phagosome Rubicon tuberculosis |
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