期刊
STEM CELL REPORTS
卷 14, 期 5, 页码 940-955出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2020.04.001
关键词
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资金
- Wellcome Trust [WTISSF121302, 090532/Z/09/Z]
- Oxford Martin School [LC0910-004]
- MRC Dementias Platform UK Stem Cell Network Capital Equipment [MC_EX_MR/N50192X/1, MR/N013255/1, MC_PC_16034]
- ARUK Oxford Network pump-priming award
- Innovative Medicines Initiative Joint Undertaking [115439]
- European Union
- EFPIA companies
- MRC Hub [G0900747 91070]
- Monument Trust Discovery award from Parkinson UK, a charity registered in England and Wales [2581970]
- Monument Trust Discovery award from Parkinson UK, a charity registered in Scotland [SC037554]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Center based at Oxford University Hospitals NHS Trust
- University of Oxford
- NIHR Comprehensive Local Research Network
- MRC [MC_EX_MR/N50192X/1, MC_PC_16034, MR/N013255/1, MR/M024962/1, MR/L023784/1, MR/N029453/1, MR/P007058/1, MR/L023784/2] Funding Source: UKRI
The Parkinson's disease-associated gene, LRRK2, is also associated with immune disorders and infectious disease and is expressed in immune subsets. Here, we characterize a platform for interrogating the expression and function of endogenous LRRK2 in authentic human phagocytes using human induced pluripotent stem cell-derived macrophages and microglia. Endogenous LRRK2 is expressed and upregulated by interferon-g in these cells, including a 187-kDa cleavage product. Using LRRK2 knockout and G2019S isogenic repair lines, we find that LRRK2 is not involved in initial phagocytic uptake of bioparticles but is recruited to LAMP1(+)/RAB9(+) maturing phagosomes, and LRRK2 kinase inhibition enhances its residency at the phagosome. Importantly, LRRK2 is required for RAB8a and RAB10 recruitment to phagosomes, implying that LRRK2 operates at the intersection between phagosome maturation and recycling pathways in these professional phagocytes.
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