期刊
EMBO JOURNAL
卷 37, 期 12, 页码 -出版社
WILEY
DOI: 10.15252/embj.201798694
关键词
LRRK2; Parkinson's disease; phagosome; Rubicon; tuberculosis
资金
- Medical Research Council UK [MR/N026004/1, MR/L010933/1, MC_UU_12016/5, MC_UP_1202/11, FC001092]
- Boehringer Ingelheim
- GSK
- Merck KGaA
- Michael J. Fox Foundation
- Parkinson's UK Fellowship [F1002]
- Francis Crick Institute from Cancer Research UK [FC001092]
- Wellcome Trust [FC001092, WTISSF121302]
- Oxford Martin School [LC0910-004]
- Innovative Medicines Initiative Joint Undertaking (IMI JU) [115439]
- European Union's Seventh Framework Programme
- Parkinson's UK
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre
- NIHR Comprehensive Local Research Network
- EFPIA companies
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [ZIAES103286] Funding Source: NIH RePORTER
- MRC [MR/L010933/1, MC_UU_12016/4, MC_UU_12016/2, MC_UU_00018/1, MR/M024962/1, MC_UU_12016/5, MC_UU_00018/2, MR/N026004/1, MC_UP_1202/11] Funding Source: UKRI
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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