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Three-dimensional morphodynamic simulations of macropinocytic cups

ABSTRACT: Summary Macropinocytosis refers to the non-specific uptake of extracellular fluid, which plays ubiquitous roles in cell growth, immune surveillance, and virus entry. Despite its widespread occurrence, it remains unclear how its initial cup-shaped plasma membrane extensions form without any external solid support, as opposed to the process of particle uptake during phagocytosis. Here, by developing a computational framework that describes the coupling between the bistable reaction-diffusion processes of active signaling patches and membrane deformation, we demonstrated that the protrusive force localized to the edge of the patches can give rise to a self-enclosing cup structure, without further assumptions of local bending or contraction. Efficient uptake requires a balance among the patch size, magnitude of protrusive force, and cortical tension. Furthermore, our model exhibits cyclic cup formation, coexistence of multiple cups, and cup-splitting, indicating that these complex morphologies self-organize via a common mutually-dependent process of reaction-diffusion and membrane deformation. Graphical abstract Highlights • A mathematical model of macropinocytosis cup formation and closure is proposed• A self-enclosing cup emerges from reaction-diffusion pattern on a deformable membrane• Cup-like membrane deformation can arise without curvature-inducing molecules• Cup morphology variations explain the conditions and efficiency of fluid uptake Membrane architecture; Cell biology; Computer modeling

SUBMITTER: Saito N

PROVIDER: S-EPMC8560551 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A plasma membrane template for macropinocytic cups.

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| S-EPMC5154761 | biostudies-literature

Formation and closure of macropinocytic cups in Dictyostelium.

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| S-EPMC7614961 | biostudies-literature

Coordinated Ras and Rac Activity Shapes Macropinocytic Cups and Enables Phagocytosis of Geometrically Diverse Bacteria.

Project description: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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Diagnostic and Therapeutic Maneuvers for Anterior Canal BPPV Canalithiasis: Three-Dimensional Simulations.

Project description:Background and Objectives: Anterior canal BPPV is a rare BPPV variant. Various diagnostic and therapeutic maneuvers have been described for its management. The aim of this study was to use three-dimensional simulation models to visualize otoconial debris movement within the anterior canal during diagnostic tests and different liberatory maneuvers. This can help to optimize existing treatment maneuvers and help in the development of better management protocols. Methods: Based on reconstructed MRI images and fluid dynamics, a 3D dynamic simulation model (as a function of time) was developed and applied. Simulations of the supine head-hanging test for diagnosis of ac-BPPV were studied. Three repositioning maneuvers were simulated: 1) the Yacovino maneuver and its modifications, 2) the reverse Epley maneuver and 3) the short canal repositioning (CRP) maneuver. Results: The simulation showed that the supine head-hanging test is a good test for diagnosis of ac-BPPV affecting both labyrinths and demonstrated why there is no inversion of nystagmus on sitting up. The Yacovino maneuver was seen to be an effective treatment option for ac-BPPV without having to determine the side involved. However, simulations showed that the classical Yacovino maneuver carried a risk of canal switch to the posterior canal. To overcome this risk, a modified Yacovino maneuver is suggested. The reverse Epley maneuver was not an effective treatment. Short CRP is useful in ac-BPPV treatment; however, it requires determination of side of involvement. Conclusion: The 3D simulator of the movement of the otoconial debris presented here can be used to test the mechanism of action and the theoretical efficacy of existing diagnostic tests and maneuvers as well as to develop new treatment maneuvers to optimize BPPV treatment.

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