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

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

doi:10.1016/j.stemcr.2020.04.001

Cited by 70 publications

(55 citation statements)

References 58 publications

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“…Several recently published reports have localized Rab10 recruitment to late endolysosomes (Eguchi et al , ; Lee et al , ). In contrast to these studies, we localized Rab10 recruitment on early macropinosomes loaded with soluble dextran in macrophage cells.…”

Section: Discussionmentioning

confidence: 99%

LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes

Zhao

et al. 2020

The EMBO Journal

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Genetic variation in LRRK2 associates with the susceptibility to Parkinson's disease, Crohn's disease, and mycobacteria infection. High expression of LRRK2 and its substrate Rab10 occurs in phagocytic cells in the immune system. In mouse and human primary macrophages, dendritic cells, and microglia-like cells, we find that Rab10 specifically regulates a specialized form of endocytosis known as macropinocytosis, without affecting phagocytosis or clathrin-mediated endocytosis. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GTP-Rab10, before EEA1 and Rab5 recruitment to early macropinosomes occurs. Macropinosome cargo in macrophages includes CCR5, CD11b, and MHCII, and LRRK2-phosphorylation of Rab10 potently blocks EHBP1L1-mediated recycling tubules and cargo turnover. EHBP1L1 overexpression competitively inhibits LRRK2-phosphorylation of Rab10, mimicking the effects of LRRK2 kinase inhibition in promoting cargo recycling. Both Rab10 knockdown and LRRK2 kinase inhibition potently suppress the maturation of macropinosome-derived CCR5-loaded signaling endosomes that are critical for CCL5-induced immunological responses that include Akt activation and chemotaxis. These data support a novel signaling axis in the endolysosomal system whereby LRRK2-mediated Rab10 phosphorylation stalls vesicle fast recycling to promote PI3K-Akt immunological responses.

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Section: Discussionmentioning

confidence: 99%

LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes

Zhao

et al. 2020

The EMBO Journal

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“…Recent work from our lab and others have shown that under specific stimuli, LRRK2 can be targeted to different membranous compartments where it can phosphorylate and recruit several Rab substrates. For example, LRRK2 has been robustly shown to translocate to the TGN, the phagosomal membrane and the membrane of damaged lysosomes depending on the stimulus used(Beilina et al, 2014;Herbst et al, 2020;Lee et al, 2020;Eguchi et al, 2018;Bonet-Ponce et al, 2020;Purlyte et al, 2019). However, the dynamics underlying LRRK2 membrane presence, activation and Rab phosphorylation remain unclear and, specifically, whether membrane association is necessary or sufficient for LRRK2 activation.…”

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confidence: 99%

Lysosomal positioning regulates Rab10 phosphorylation at LRRK2-positive lysosomes

Kluss

Beilina

Lewis

et al. 2020

Preprint

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Genetic variation at the Leucine-rich repeat kinase 2 (LRRK2) locus contributes to risk of familial and sporadic Parkinson disease. Recent data have shown a robust association between localization to various membranes of the endolysosomal system and LRRK2 activation. However, the mechanism(s) underlying LRRK2 activation at endolysosomal membranes are still poorly understood. Here we artificially direct LRRK2 to six different membranes within the endolysosomal system. We demonstrate that LRRK2 is activated and able to phosphorylate three of its Rab substrates (Rab10, Rab12 and Rab29) at each compartment. However, we report differing localization of pRab10 and pRab12 at the lysosomal and Golgi membranes. Specifically, we found that pRab10 colocalizes with a sub-population of perinuclear LRRK2-positive Golgi/lysosomal compartments whereas pRab12 localized to all LRRK2-positive Golgi/lysosomal membranes across the cell. When organelle positioning is manipulated by sequestering lysosomes to the perinuclear area, pRab10 colocalization with LRRK2 significantly increases. We also show recruitment of JIP4, a pRab10 effector that we have recently linked to LYTL, after trapping LRRK2 at various membranes. Taken together, we demonstrate that the association of LRRK2 to membranous compartments is sufficient for its activation and Rab phosphorylation independent of membrane identity. Our system also identifies a potential mechanism underlying the distinct relationships between LRRK2 and its substrates Rab10 and Rab12.

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“…No studies reporting significant defects in microglia‐like cells carrying PD‐related mutations have been published so far. The studies using iPSC‐derived monocytes/macrophages have not reported strong phenotypes either, 75,76 except in macrophages carrying SNCA triplication mutations 77 and GBA1 mutation, 78 both causing impairment in phagocytosis and elevated production of inflammatory cytokines. A very recent study using iPSC‐derived macrophages and microglia‐like cells has shown that LRRK2 is upregulated by IFN‐γ stimulation and is recruited to maturing phagosomes 75 .…”

Section: Microgliamentioning

confidence: 99%

Metabolic and immune dysfunction of glia in neurodegenerative disorders: Focus on iPSC models

et al. 2020

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The research on neurodegenerative disorders has long focused on neuronal pathology and used transgenic mice as disease models. However, our understanding of the chronic neurodegenerative process in the human brain is still very limited. It is increasingly recognized that neuronal loss is not caused solely by intrinsic degenerative processes but rather via impaired interactions with surrounding glia and other brain cells. Dysfunctional astrocytes do not provide sufficient nutrients and antioxidants to the neurons, while dysfunctional microglia cannot efficiently clear pathogens and cell debris from extracellular space, thus resulting in chronic inflammatory processes in the brain. Importantly, human glia, especially the astrocytes, differ significantly in morphology and function from their mouse counterparts, and therefore more human‐based disease models are needed. Recent advances in stem cell technology make it possible to reprogram human patients' somatic cells to induced pluripotent stem cells (iPSC) and differentiate them further into patient‐specific glia and neurons, thus providing a virtually unlimited source of human brain cells. This review summarizes the recent studies using iPSC‐derived glial models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and discusses the applicability of these models to drug testing. This line of research has shown that targeting glial metabolism can improve the survival and function of cocultured neurons and thus provide a basis for future neuroprotective treatments.

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

Cited by 70 publications

References 58 publications

LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes

LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes

Lysosomal positioning regulates Rab10 phosphorylation at LRRK2-positive lysosomes

Metabolic and immune dysfunction of glia in neurodegenerative disorders: Focus on iPSC models

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