LRRK2 Is Recruited to Phagosomes and Co-recruits RAB8 and RAB10 in Human Pluripotent Stem Cell-Derived Macrophages
| Autor: | Phillippa J. Carling, William James, Rowan Flynn, Walther Haenseler, Monika Stegmann, Jane Vowles, Heyne Lee, Sally A. Cowley, Francesca J. Nicholls, Ishta Sharma, Emma R. Haberman, Richard Wade-Martins |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Parkinson's disease Phagocytosis Induced Pluripotent Stem Cells microglia macrophage Biology Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Biochemistry Article Cell Line Interferon-gamma 03 medical and health sciences 0302 clinical medicine Immune system Phagosomes RAB8 Phagosome maturation Genetics medicine Humans human Induced pluripotent stem cell Phagosome iPSC LAMP1 Microglia Macrophages phagocytosis LRRK2 Cell Differentiation Cell Biology RAB nervous system diseases Cell biology 030104 developmental biology medicine.anatomical_structure rab GTP-Binding Proteins RAB10 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2020.04.001 |
| Popis: | Summary 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-γ 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. Graphical Abstract Highlights • Human iPSC macrophages and microglia for studying endogenous LRRK2 function • LRRK2 is not involved in initial phagocytic uptake of bioparticles • LRRK2 is recruited to LAMP1+/RAB9+ “maturing” phagosomes • LRRK2 is required for RAB8a and RAB10 recruitment to phagosomes Cowley et al. use patient, control, and gene-edited human iPSC macrophages/microglia to examine endogenous expression and function of the Parkinson's disease gene, LRRK2, in this immune subset. LRRK2 is not involved in initial phagocytic uptake of bioparticles but is recruited to LAMP1+/RAB9+ “maturing” phagosomes and is required for RAB8a and RAB10 recruitment to phagosomes, linking phagosome maturation to recycling pathways. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|