PAG3/Papα/KIAA0400, a GTPase-activating protein for ADP-ribosylation factor (ARF), regulates ARF6 in Fcγ receptor-mediated phagocytosis of macrophages

Hiroshi Uchida, Akiko Kondo, Yasunori Yoshimura, Yuichi Mazaki, Hisataka Sabe

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The Fcγ receptor (FcγR)-mediated phagocytosis of macrophages is a complex process where remodeling of both the actin-based cytoskeleton and plasma membrane occur coordinately. Several different families of small GTPases are involved. We have isolated a GTPase-activating protein (GAP) for ADP-ribosylation factor (ARF), paxillin-associated protein with ARFGAP activity (PAG)3/Papα/KIAA0400, from mature monocytes and macrophage-like cells. Mammalian ARFs fall into three classes, and the class III isoform (ARF6) has been shown to be involved in FcγR-mediated phagocytosis. Here we report that PAG3 is enriched together with ARF6 and F-actin at phagocytic cups formed beneath immunoglobulin G-opsonized beads in P388D1 macrophages, in which overexpression of ARF6, but not ARF1 (class I) or ARF5 (class II), inhibits the phagocytosis. Overexpression of PAG3, but not its GAP-inactive mutant, attenuated the focal accumulation of F-actin and blocked phagocytosis, although surface levels of the FcγRs were not affected. Other ubiquitously expressed ARFGAPs, G protein-coupled receptor kinase interactors GIT2 and GIT2-short/KIAA0148, which we have shown to exhibit GAP activity for ARF1 in COS-7 cells, did not accumulate at the phagocytic cups or inhibit phagocytosis. Moreover, cooverexpression of ARF6, but not ARF1 or ARF5, restored the phagocytic activity of PAG3-overexpressing cells. We propose that PAG3 acts as a GAP for ARF6 and is hence involved in FcγR-mediated phagocytosis in mouse macrophages.

Original languageEnglish
Pages (from-to)955-966
Number of pages12
JournalJournal of Experimental Medicine
Volume193
Issue number8
DOIs
Publication statusPublished - 2001 Apr 16

Keywords

  • ARF family GTPases
  • ARFGAP
  • Actin remodeling
  • Membrane remodeling
  • Rho family GTPases

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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