Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins

Daniel Schlam; Richard D. Bagshaw; Spencer A. Freeman; Richard F. Collins; Tony Pawson; Gregory D. Fairn; Sergio Grinstein

doi:10.1038/ncomms9623

Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins

Daniel Schlam, Richard D. Bagshaw, Spencer A. Freeman, Richard F. Collins, Tony Pawson, Gregory D. Fairn, Sergio Grinstein

Research output: Contribution to journal › Article › peer-review

155 Citations (Scopus)

Abstract

Phagocytosis is responsible for the elimination of particles of widely disparate sizes, from large fungi or effete cells to small bacteria. Though superficially similar, the molecular mechanisms involved differ: engulfment of large targets requires phosphoinositide 3-kinase (PI3K), while that of small ones does not. Here, we report that inactivation of Rac and Cdc42 at phagocytic cups is essential to complete internalization of large particles. Through a screen of 62 RhoGAP-family members, we demonstrate that ARHGAP12, ARHGAP25 and SH3BP1 are responsible for GTPase inactivation. Silencing these RhoGAPs impairs phagocytosis of large targets. The GAPs are recruited to large - but not small - phagocytic cups by products of PI3K, where they synergistically inactivate Rac and Cdc42. Remarkably, the prominent accumulation of phosphatidylinositol 3,4,5-trisphosphate characteristic of large-phagosome formation is less evident during phagocytosis of small targets, accounting for the contrasting RhoGAP distribution and the differential requirement for PI3K during phagocytosis of dissimilarly sized particles.

Original language	English
Article number	8623
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9623
Publication status	Published - Oct 14 2015
Externally published	Yes

Bibliographical note

Funding Information:
D.S. was supported by a Cystic Fibrosis Canada graduate studentship (award ID: 2704) and is currently funded by a Restracomp studentship from The Hospital for Sick Children. S.A.F. is funded by a fellowship from the Heart and Stroke Foundation of Canada. This work was supported by grants from the Canadian Institutes of Health Research (MOP-7075).

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms9623

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title = "Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins",

abstract = "Phagocytosis is responsible for the elimination of particles of widely disparate sizes, from large fungi or effete cells to small bacteria. Though superficially similar, the molecular mechanisms involved differ: engulfment of large targets requires phosphoinositide 3-kinase (PI3K), while that of small ones does not. Here, we report that inactivation of Rac and Cdc42 at phagocytic cups is essential to complete internalization of large particles. Through a screen of 62 RhoGAP-family members, we demonstrate that ARHGAP12, ARHGAP25 and SH3BP1 are responsible for GTPase inactivation. Silencing these RhoGAPs impairs phagocytosis of large targets. The GAPs are recruited to large - but not small - phagocytic cups by products of PI3K, where they synergistically inactivate Rac and Cdc42. Remarkably, the prominent accumulation of phosphatidylinositol 3,4,5-trisphosphate characteristic of large-phagosome formation is less evident during phagocytosis of small targets, accounting for the contrasting RhoGAP distribution and the differential requirement for PI3K during phagocytosis of dissimilarly sized particles.",

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Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins

Abstract

Bibliographical note

ASJC Scopus Subject Areas

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