Journal
CURRENT BIOLOGY
Volume 30, Issue 15, Pages 2912-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2020.05.049
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Funding
- Royal Society University Research Fellowship [UF140624]
- BBSRC White Rose PhD studentship [BB/J014443/1]
- MRC-Discovery Medicine North (DiMEN) studentship [MR/N013840/1]
- UK Medical Research Council [G0700091]
- Wellcome Trust [GR077544AIA]
- MRC [MC_U105115237]
- Swiss National Science Foundation [310030_149390]
- Swiss National Science Foundation (SNF) [310030_149390] Funding Source: Swiss National Science Foundation (SNF)
- MRC [G0700091, MC_U105115237] Funding Source: UKRI
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Engulfment of extracellular material by phagocytosis or macropinocytosis depends on the ability of cells to generate specialized cup-shaped protrusions. To effectively capture and internalize their targets, these cups are organized into a ring or ruffle of actin-driven protrusion encircling a non-protrusive interior domain. These functional domains depend on the combined activities of multiple Ras and Rho family small GTPases, but how their activities are integrated and differentially regulated over space and time is unknown. Here, we show that the amoeba Dictyostelium discoideum coordinates Ras and Rac activity using the multidomain protein RGBARG (RCC1, RhoGEF, BAR, and RasGAP-containing protein). We find RGBARG uses a tripartite mechanism of Ras, Rac, and phospholipid interactions to localize at the protruding edge and interface with the interior of both macropinocytic and phagocytic cups. There, we propose RGBARG shapes the protrusion by expanding Rac activation at the rim while suppressing expansion of the active Ras interior domain. Consequently, cells lacking RGBARG form enlarged, flat interior domains unable to generate large macropinosomes. During phagocytosis, we find that disruption of RGBARG causes a geometry-specific defect in engulfing rod-shaped bacteria and ellipsoidal beads. This demonstrates the importance of coordinating small GTPase activities during engulfment of more complex shapes and thus the full physiological range of microbes, and how this is achieved in a model professional phagocyte.
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