LRRK2 Is Recruited to Phagosomes and Co-recruits RAB8 and RAB10 in Human Pluripotent Stem Cell-Derived Macrophages.

Heyne Lee, Rowan Flynn, Ishta Sharma, Emma Haberman, Phillippa J Carling, Francesca J Nicholls, Monika Stegmann, Jane Vowles, Walther Haenseler, Richard Wade-Martins, William S James, Sally A Cowley

Stem cell reports 2020 May 12

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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. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Heyne Lee, Rowan Flynn, Ishta Sharma, Emma Haberman, Phillippa J Carling, Francesca J Nicholls, Monika Stegmann, Jane Vowles, Walther Haenseler, Richard Wade-Martins, William S James, Sally A Cowley. LRRK2 Is Recruited to Phagosomes and Co-recruits RAB8 and RAB10 in Human Pluripotent Stem Cell-Derived Macrophages. Stem cell reports. 2020 May 12;14(5):940-955