LRRK2 is recruited to phagosomes and co-recruits Rab8 and Rab10 in human pluripotent stem cell-derived macrophages

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

doi:10.1101/779835

Cited by 17 publications

(27 citation statements)

References 58 publications

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“…However, in consideration of past reports, we acknowledge that other Rab proteins may eventually compensate for the loss of Rab10 with probable broader effects on endocytosis and vesicle traffic (Schuck et al, 2007). Several recently published reports have localized Rab10 recruitment to late endolysosomes (Eguchi et al, 2018;Lee et al, 2020). In contrast to these studies, we localized Rab10 recruitment on early macropinosomes loaded with soluble dextran in macrophage cells.…”

Section: Discussionmentioning

confidence: 75%

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: 75%

LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes

Zhao

et al. 2020

The EMBO Journal

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“…Indeed, activation of TLR4 with LPS causes a redistribution of LRRK2 to membrane structures (Schapansky et al, 2014), and LRRK2 localizes to phagosome structures in monocytes infected with S. typhimurium (Gardet et al, 2010). LRRK2 is also required for co-recruitment of Rab proteins to late phagosomes in human IPS-derived macrophages exposed to different TLR2 and TLR4 activating pathogens (Lee et al, 2019). Further details of what occurs downstream of LRRK2 in TLR signaling remain to be elucidated, but phosphorylation of substrate Rab proteins is likely of interest given the published roles they may play in TLR biology (Wang et al, 2010;Luo et al, 2014).…”

Section: Lrrk2 and Toll-like Receptor Signalingmentioning

confidence: 99%

“…However, overexpression of LRRK2 has also been demonstrated to increase NFAT transcriptional activity in bone marrow derived dendritic cells (Takagawa et al, 2018), complicating the original interpretation of LRRK2 as a negative regulator of NFAT. Zymosan has also been shown to increase LRRK2 Ser910 andSer935 phosphorylation and LRRK2 localization Lee et al, 2019), although these effects are potentially mediated via TLR2 rather than dectin-1.…”

Section: Lrrk2 and C-type Lectin Signalingmentioning

confidence: 99%

“…That the host response to different pathogens that infect different cell types in different manners can be either positively or negatively impacted by LRRK2 function certainly complicates research in this area. In terms of mechanistic insight, studies to date suggest that LRRK2 may modulate the uptake, trafficking and lysosomal degradation of pathogens, impact upon mitochondrial function thereby reducing the capacity of reactive oxygen species to target pathogens and/or modulate inflammatory responses through the regulation of immune signaling pathways such as the inflammasome (Gardet et al, 2010;Zhang et al, 2015;Liu W. et al, 2017;Hartlova et al, 2018;Herbst and Gutierrez, 2019;Lee et al, 2019).…”

Section: Lrrk2 and Pathogen Clearancementioning

confidence: 99%

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Leucine Rich Repeat Kinase 2 and Innate Immunity

Rastegar

Dzamko

2020

Front. Neurosci.

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For more than a decade, researchers have sought to uncover the biological function of the enigmatic leucine rich repeat kinase 2 (LRRK2) enzyme, a large multi-domain protein with dual GTPase and kinase activities. Originally identified as a familial Parkinson's disease (PD) risk gene, variations in LRRK2 are also associated with risk of idiopathic PD, inflammatory bowel disease and susceptibility to bacterial infections. LRRK2 is highly expressed in peripheral immune cells and the potential of LRRK2 to regulate immune and inflammatory pathways has emerged as common link across LRRK2implicated diseases. This review outlines the current genetic and biochemical evidence linking LRRK2 to the regulation of innate immune inflammatory pathways, including the toll-like receptor and inflammasome pathways. Evidence suggests a complex interplay between genetic risk and protective alleles acts to modulate immune outcomes in a manner dependent on the particular pathogen and cell type invaded.

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“…These derived microglial cells acquired a highly dynamic ramified morphology and exhibited neuronal surveillance activity mimicking the in vivo situation. Building on this advancement, a subsequent study demonstrated that LRRK2 expression in macrophages and microglia plays an important role in phagosome maturation and in the regulation of recycling pathways, implying that LRRK2 mutations in PD patients may disrupt microglial clearance mechanisms [ 131 ]. Additionally, it has been shown that the LRRK2-G2019S mutation influences fate decision in hiPSC-derived human monocytes, further endorsing the involvement of the immune system in the development of PD [ 132 ].…”

Section: Looking Into the Future: Optimization Of Hipsc-based Modementioning

confidence: 99%

Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson’s Disease for Drug Identification

Kouroupi

Antoniou

Prodromidou

et al. 2020

IJMS

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Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by loss of striatal-projecting dopaminergic neurons of the ventral forebrain, resulting in motor and cognitive deficits. Despite extensive efforts in understanding PD pathogenesis, no disease-modifying drugs exist. Recent advances in cell reprogramming technologies have facilitated the generation of patient-derived models for sporadic or familial PD and the identification of early, potentially triggering, pathological phenotypes while they provide amenable systems for drug discovery. Emerging developments highlight the enhanced potential of using more sophisticated cellular systems, including neuronal and glial co-cultures as well as three-dimensional systems that better simulate the human pathophysiology. In combination with high-throughput high-content screening technologies, these approaches open new perspectives for the identification of disease-modifying compounds. In this review, we discuss current advances and the challenges ahead in the use of patient-derived induced pluripotent stem cells for drug discovery in PD. We address new concepts implicating non-neuronal cells in disease pathogenesis and highlight the necessity for functional assays, such as calcium imaging and multi-electrode array recordings, to predict drug efficacy. Finally, we argue that artificial intelligence technologies will be pivotal for analysis of the large and complex data sets obtained, becoming game-changers in the process of drug discovery.

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LRRK2 is recruited to phagosomes and co-recruits Rab8 and Rab10 in human pluripotent stem cell-derived macrophages

Cited by 17 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

Leucine Rich Repeat Kinase 2 and Innate Immunity

Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson’s Disease for Drug Identification

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