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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • GTPase-Activating Proteins / metabolism
  • Healthy Volunteers
  • Humans
  • Phagocytosis*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • rho GTP-Binding Proteins / metabolism*

Substances

  • Actins
  • GTPase-Activating Proteins
  • Rho Guanine Nucleotide Exchange Factors
  • rho GTPase-activating protein
  • Phosphatidylinositol 3-Kinases
  • rho GTP-Binding Proteins