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Download fileLRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
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posted on 2020-08-05, 16:34 authored by Anetta Härtlova, Susanne Herbst, 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 GutierrezMutations 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.The EMBO Journal (2018) e98694
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LRRK2Parkinson's diseaseRubiconphagosometuberculosisAnimalsAutophagy-Related ProteinsHumansIntracellular Signaling Peptides and ProteinsLeucine-Rich Repeat Serine-Threonine Protein Kinase-2MacrophagesMiceMice, KnockoutMycobacterium tuberculosisPhagosomesPhosphatidylinositol 3-KinasesTuberculosisGutierrez FC001092GSK06 Biological Sciences08 Information and Computing Sciences11 Medical and Health SciencesDevelopmental Biology