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

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 (Lead / Corresponding author), Maximiliano G. Gutierrez (Lead / Corresponding author)

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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.

Original languageEnglish
Article numbere98694
Pages (from-to)1-17
Number of pages17
JournalThe EMBO Journal
Volume37
Issue number12
Early online date22 May 2018
DOIs
Publication statusPublished - 15 Jun 2018

Keywords

  • LRRK2
  • Parkinson's disease
  • Rubicon
  • phagosome
  • tuberculosis

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    Härtlova, A., Herbst, S., Peltier, J., Rodgers, A., Bilkei-Gorzo, O., Fearns, A., Dill, B. D., Lee, H., Flynn, R., Cowley, S. A., Davies, P., Lewis, P. A., Ganley, I. G., Martinez, J., Alessi, D. R., Reith, A. D., Trost, M., & Gutierrez, M. G. (2018). LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages. The EMBO Journal, 37(12), 1-17. [e98694]. https://doi.org/10.15252/embj.201798694