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

Hartlova, A., Herbst, S., Peltier, J., Rodgers, A., Bilkei-Gorzo, O., Fearns, A., Dill, B. D., Lee, H., Rowan, F., Cowley, S. A., Davies, P., Lewis, P. A., Ganley, I. G., Martinez, J., Alessi, D. R., Reith, A. D., Trost, M. and Gutierrez, M. G. (2018) LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages. The EMBO Journal, 37 (12). e98694. ISSN 0261-4189 doi: 10.15252/embj.201798694

Abstract/Summary

Mutations in the leucine-rich repeat kinase 2 (LRRK2) are associ- ated with Parkinson’s disease, chronic inflammation and mycobac- terial 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 mycobac- terial control independently of autophagy. In vivo, LRRK2 defi- ciency 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 replica- tion by regulating phagosome maturation.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/77585
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	EMBO Press
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