LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes

Abstract

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.

Rab10-Positive Tubular Structures Represent a Novel Endocytic Pathway That Diverges From Canonical Macropinocytosis in RAW264 Macrophages

“…Recently, Liu et al (19) reported the transitional association of Rab10 with early macropinosomes in RAW macrophages. In their study, the LRRK2-mediated phosphorylation of Rab10 was shown to play a regulatory role in macropinosome maturation (19). However, they did not mention the formation of Rab10positive tubules derived from the premacropinosomes that are persistently Rab10-positive.…”

“…More recently, Rab10 was identified as a novel protein regulator of tubular recycling endosome formation through interaction with the kinesin motor protein KIF13 (18). Furthermore, it was reported that Rab10 phosphorylation by leucine-rich repeat kinase 2 (LRRK2) has been associated with the regulation of macropinosome early maturation (19).…”

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.…”

Rab10-positive tubular structures represent a novel endocytic pathway that diverges from canonical macropinocytosis in RAW264 macrophages

“…Recently, Liu et al (2020) reported the transitional association of Rab10 with early macropinosomes in RAW macrophages. In their study, the LRRK2-mediated phosphorylation of Rab10 was shown to play a regulatory role in macropinosome maturation (18). However, they did not mention the formation of Rab10-positive tubules derived from the premacropinosomes that is persistently Rab10-positive.…”

“…More recently, Rab10 was identified as a novel protein regulator of tubular recycling endosome formation through interaction with the kinesin motor protein KIF13 (17). Furthermore, it was reported that Rab10 phosphorylation by leucine-rich repeat kinase 2 (LRRK2) has been associated with the regulation of macropinosome early maturation (18).…”