Abstract
BackgroundThe uptake of particles by actin-powered invagination of the plasma membrane is common to protozoa and to phagocytes involved in the immune response of higher organisms. The question addressed here is how a phagocyte may use geometric cues to optimize force generation for the uptake of a particle. We survey mechanisms that enable a phagocyte to remodel actin organization in response to particles of complex shape.ResultsUsing particles that consist of two lobes separated by a neck, we found that Dictyostelium cells transmit signals concerning the curvature of a surface to the actin system underlying the plasma membrane. Force applied to a concave region can divide a particle in two, allowing engulfment of the portion first encountered. The phagosome membrane that is bent around the concave region is marked by a protein containing an inverse Bin-Amphiphysin-Rvs (I-BAR) domain in combination with an Src homology (SH3) domain, similar to mammalian insulin receptor tyrosine kinase substrate p53. Regulatory proteins enable the phagocyte to switch activities within seconds in response to particle shape. Ras, an inducer of actin polymerization, is activated along the cup surface. Coronin, which limits the lifetime of actin structures, is reversibly recruited to the cup, reflecting a program of actin depolymerization. The various forms of myosin-I are candidate motor proteins for force generation in particle uptake, whereas myosin-II is engaged only in retracting a phagocytic cup after a switch to particle release. Thus, the constriction of a phagocytic cup differs from the contraction of a cleavage furrow in mitosis.ConclusionsPhagocytes scan a particle surface for convex and concave regions. By modulating the spatiotemporal pattern of actin organization, they are capable of switching between different modes of interaction with a particle, either arresting at a concave region and applying force in an attempt to sever the particle there, or extending the cup along the particle surface to identify the very end of the object to be ingested. Our data illustrate the flexibility of regulatory mechanisms that are at the phagocyte's disposal in exploring an environment of irregular geometry.
Highlights
Phagocytes, as macrophages, neutrophils or Dictyostelium cells, respond to the shape of surfaces they encounter
Actin accumulation and force generation at concave particle surfaces To monitor the dynamics of actin accumulation around a particle consisting of convex and concave surfaces, we used Dictyostelium phagocytes expressing a label for filamentous actin, LimEΔ-green- fluorescent protein (GFP) [29], and exposed the cells to particles of a yeast mutant arrested in budding, which causes the yeast to assume an hourglass shape
Switching between two modes of interaction with a particle of complex shape The membrane of a phagocytic cup is distinguished from the surrounding plasma membrane by the enrichment of PI(3,4,5)P3 (PIP3) [30,31]
Summary
Phagocytes, as macrophages, neutrophils or Dictyostelium cells, respond to the shape of surfaces they encounter. At the end of uptake, the cup closes on top of the particle by membrane separation and fusion. In this way, the inner surface of the cup becomes the phagosome. Actin polymerization at the edge of the phagocytic cup drives protrusion and mediates the contractile activity that is responsible for closing the cup on top of the particle. This contractile activity has been illustrated by pairs of macrophages attempting to engulf a single erythrocyte [2]. We survey mechanisms that enable a phagocyte to remodel actin organization in response to particles of complex shape
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