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

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

  • Nat Commun. 2015 Oct 14;6:8623. doi: 10.1038/ncomms9623.
Daniel Schlam 1 2,  Richard D Bagshaw 3,  Spencer A Freeman 1,  Richard F Collins 1,  Tony Pawson 3,  Gregory D Fairn 2 4,  Sergio Grinstein 1 2 4
Affiliations

Affiliations

  • 1 Division of Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G1X8.
  • 2 Institute of Medical Science, University of Toronto, Faculty of Medicine, 1 King's College Circle, Toronto, Ontario, Canada M5S1A8.
  • 3 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G1X5.
  • 4 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, 209 Victoria Street, Toronto, Ontario, Canada M5B1T8.
PMID: 26465210 DOI: 10.1038/ncomms9623
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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