LRRK2 and Rab10 Coordinate Macropinocytosis to Mediate Immunological Responses in Phagocytes

Abstract

Genetic variation in LRRK2 associates with susceptibility to Parkinson's disease, Crohn's disease, and mycobacteria infection, with high expression of LRRK2, and the LRRK2 kinase substrate Rab10, in phagocytic cells in the immune system. In mouse and human primary monocyte-derived 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)P 3 -positive GTP-Rab10 early macropinosomes, before EEA1 and Rab5 recruitment occurs. Macropinosome cargo in macrophages includes CCR5, CD11b, and MHCII, with LRRK2-phosphorylation of Rab10 potently blocking EHBP1L1-mediated recycling tubules and cargo turnover. EHBP1L1 over-expression 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 suppresses the maturation of macropinosome-derived CCR5-loaded signaling endosomes important for CCL5-induced AKT-activation and chemotaxis. These data support a novel axis in the endolysosomal system whereby LRRK2-mediated Rab10 phosphorylation stalls vesicle fast-recycling to promote PI3K-AKT signal transduction.

Parkinson’s Disease–Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance

“…Our study revealed that the most common pathogenic mutation in LRRK2, G2019S, negatively regulates the amount of engulfed fibrillar α-syn in astrocytes. In agreement with our evidence, it has recently been proposed that LRRK2 kinase activity blocks micropinocytosis in phagocytes through the phosphorylation of Rab10 [27]. Analyzing the differently sized α-syn inclusions separately revealed that the reduced αsyn accumulation in Lrrk2 GS/GS astrocytes was predominantly driven by the small α-syn inclusions.…”

“…However, LRRK2 has also been shown to impair phagosome maturation in macrophages [25], and to be recruited at later stages of the internalization in macrophages and microglia [26], indicating that a clear understanding of LRRK2's role in phagocytosis is missing. Of note, a recent report indicates that LRRK2 negatively regulates the clearance of extracellular particles via macropinocytosis [27].…”

Parkinson’s Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance

“…Our study revealed that the most common pathogenic mutation in LRRK2, G2019S, negatively regulates the amount of engulfed fibrillar α-syn in astrocytes. In agreement with our evidence, it has recently been proposed that LRRK2 kinase activity blocks micropinocytosis in phagocytes through the phosphorylation of Rab10 [27]. Analyzing the differently sized α-syn inclusions separately revealed that the reduced α-syn accumulation in Lrrk2 GS/GS astrocytes was predominantly driven by the small α-syn inclusions.…”

“…However, LRRK2 has also been shown to impair phagosome maturation in macrophages [25], and to be recruited at later stages of the internalization in macrophages and microglia [26], indicating that a clear understanding of LRRK2's role in phagocytosis is missing. Of note, a recent report indicates that LRRK2 negatively regulates clearance of extracellular particles via macropinocytosis [27].…”

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

“…The LRRK2-G2019S mutation has a variable penetrance and is associated with both sporadic and familial PD. There is evidence that LRRK2 is capable of regulating macrophage and microglial motility and phagocytosis (118), mediated by RAB10 (119,120). WAVE2, a novel interacting partner with LRRK2, regulates branched actin and the Rac1 effector molecule thereby promoting actin polymerisation and cytoskeletal reorganisation.…”