ADP ribosylation factor 6 is activated and controls membrane delivery during phagocytosis in macrophages

Engulfment of particles by phagocytes is induced by their interaction with specific receptors on the cell surface, which leads to actin polymerization and the extension of membrane protrusions to form a closed phagosome. Membrane delivery from internal pools is considered to play an important role in pseudopod extension during phagocytosis. Here, we report that endogenous ADP ribosylation factor 6 (ARF6), a small GTP-binding protein, undergoes a sharp and transient activation in macrophages when phagocytosis was initiated via receptors for the Fc portion of immunoglobulins (FcRs). A dominant-negative mutant of ARF6 (T27N mutation) dramatically affected FcR-mediated phagocytosis. Expression of ARF6-T27N lead to a reduction in the focal delivery of vesicle-associated membrane protein 3+ endosomal recycling membranes at phagocytosis sites, whereas actin polymerization was unimpaired. This resulted in an early blockade in pseudopod extension and accumulation of intracellular vesicles, as observed by electron microscopy. We conclude that ARF6 is a major regulator of membrane recycling during phagocytosis.

[1]  C. D’Souza-Schorey,et al.  Modulation of Rac1 and ARF6 Activation during Epithelial Cell Scattering* , 2003, The Journal of Biological Chemistry.

[2]  S. Grinstein,et al.  Differential Role of Actin, Clathrin, and Dynamin in Fcγ Receptor-mediated Endocytosis and Phagocytosis* , 2003, The Journal of Biological Chemistry.

[3]  S. Grinstein,et al.  Inhibition of Phosphatidylinositol-4-phosphate 5-Kinase Iα Impairs Localized Actin Remodeling and Suppresses Phagocytosis* , 2002, The Journal of Biological Chemistry.

[4]  Y. Bailly,et al.  Calcium-regulated exocytosis of dense-core vesicles requires the activation of ADP-ribosylation factor (ARF)6 by ARF nucleotide binding site opener at the plasma membrane , 2002, The Journal of cell biology.

[5]  R. Houlgatte,et al.  A conserved C-terminal domain of EFA6-family ARF6-guanine nucleotide exchange factors induces lengthening of microvilli-like membrane protrusions. , 2002, Journal of cell science.

[6]  Alan Aderem,et al.  How to Eat Something Bigger than Your Head , 2002, Cell.

[7]  Etienne Gagnon,et al.  Endoplasmic Reticulum-Mediated Phagocytosis Is a Mechanism of Entry into Macrophages , 2002, Cell.

[8]  J. Pessin,et al.  Rate and extent of phagocytosis in macrophages lacking vamp3 , 2002, Journal of leukocyte biology.

[9]  S. Grinstein,et al.  Localized Exocytosis of Primary (Lysosomal) Granules During Phagocytosis: Role of Ca2+-Dependent Tyrosine Phosphorylation and Microtubules1 , 2002, The Journal of Immunology.

[10]  A. Hall,et al.  Vav regulates activation of Rac but not Cdc42 during FcγR-mediated phagocytosis , 2002 .

[11]  S. Grinstein,et al.  Phagocytosis and innate immunity. , 2002, Current opinion in immunology.

[12]  A. Lupas,et al.  Calreticulin and calnexin in the endoplasmic reticulum are important for phagocytosis , 2001, The EMBO journal.

[13]  S Grinstein,et al.  Membrane dynamics in phagocytosis. , 2001, Seminars in immunology.

[14]  P. Chavrier,et al.  Actin dynamics during phagocytosis. , 2001, Seminars in immunology.

[15]  C. Turner,et al.  Cell motility: ARNOand ARF6 at the cutting edge , 2001, Current Biology.

[16]  John G. Collard,et al.  An essential role for ARF6‐regulated membrane traffic in adherens junction turnover and epithelial cell migration , 2001, The EMBO journal.

[17]  J. Casanova,et al.  Activation of ARF6 by ARNO stimulates epithelial cell migration through downstream activation of both Rac1 and phospholipase D , 2001, The Journal of cell biology.

[18]  S. Howell,et al.  Casein Kinase I Associates with Members of the Centaurin-α Family of Phosphatidylinositol 3,4,5-Trisphosphate-binding Proteins* , 2001, The Journal of Biological Chemistry.

[19]  R. May,et al.  Phagocytosis and the actin cytoskeleton. , 2001, Journal of cell science.

[20]  J. Sirard,et al.  Entry and survival of Salmonella typhimurium in dendritic cells and presentation of recombinant antigens do not require macrophage-specific virulence factors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Grinstein,et al.  Focal Exocytosis of Vamp3-Containing Vesicles at Sites of Phagosome Formation , 2000, The Journal of cell biology.

[22]  R. Kahn,et al.  A family of ADP-ribosylation factor effectors that can alter membrane transport through the trans-Golgi. , 2000, Molecular biology of the cell.

[23]  E. Gold,et al.  Amphiphysin IIm, a novel amphiphysin II isoform, is required for macrophage phagocytosis. , 2000, Immunity.

[24]  A. Dautry‐Varsat,et al.  Mapping of Eps15 Domains Involved in Its Targeting to Clathrin-coated Pits* , 2000, The Journal of Biological Chemistry.

[25]  C. L. Jackson,et al.  Turning on ARF: the Sec7 family of guanine-nucleotide-exchange factors. , 2000, Trends in cell biology.

[26]  B. Dale,et al.  A Rab11-containing rapidly recycling compartment in macrophages that promotes phagocytosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Hall,et al.  Rho GTPases and macrophage phagocytosis. , 2000, Methods in enzymology.

[28]  E. Gold,et al.  Dynamin 2 Is Required for Phagocytosis in Macrophages , 1999, The Journal of experimental medicine.

[29]  J. Calafat,et al.  ARF6 Is Required for Growth Factor- and Rac-Mediated Membrane Ruffling in Macrophages at a Stage Distal to Rac Membrane Targeting , 1999, Molecular and Cellular Biology.

[30]  M. Frohman,et al.  Phosphatidylinositol 4-Phosphate 5-Kinase a Is a Downstream Effector of the Small G Protein ARF 6 in Membrane Ruffle Formation 1984 , 1999 .

[31]  F. Brodsky,et al.  Adp-Ribosylation Factor 6 and Endocytosis at the Apical Surface of Madin-Darby Canine Kidney Cells , 1999, The Journal of cell biology.

[32]  P. Chavrier,et al.  The role of ARF and Rab GTPases in membrane transport. , 1999, Current opinion in cell biology.

[33]  C. Tseng,et al.  A Requirement for Phosphatidylinositol 3-Kinase in Pseudopod Extension* , 1999, The Journal of Biological Chemistry.

[34]  W. Martin,et al.  Clathrin-coated pit-associated proteins are required for alveolar macrophage phagocytosis. , 1999, Journal of immunology.

[35]  A. Aderem,et al.  Mechanisms of phagocytosis in macrophages. , 1999, Annual review of immunology.

[36]  D. Nelson,et al.  Membrane capacitance changes associated with particle uptake during phagocytosis in macrophages. , 1998, Biophysical journal.

[37]  S. Grinstein,et al.  v-SNARE-dependent secretion is required for phagocytosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  C. Tseng,et al.  A Requirement for ARF6 in Fcγ Receptor-mediated Phagocytosis in Macrophages* , 1998, The Journal of Biological Chemistry.

[39]  J. Tavaré,et al.  Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes requires phosphatidylinositol 3-kinase , 1998, Current Biology.

[40]  E. V. van Donselaar,et al.  ARF6 Targets Recycling Vesicles to the Plasma Membrane: Insights from an Ultrastructural Investigation , 1998, The Journal of cell biology.

[41]  H. Radhakrishna,et al.  ADP-Ribosylation Factor 6 Regulates a Novel Plasma Membrane Recycling Pathway , 1997, The Journal of cell biology.

[42]  L. Van Aelst,et al.  A role for POR1, a Rac1‐interacting protein, in ARF6‐mediated cytoskeletal rearrangements , 1997, The EMBO journal.

[43]  K. Buttle,et al.  Phospholipase A2 inhibition results in sequestration of plasma membrane into electronlucent vesicles during IgG-mediated phagocytosis. , 1997, Journal of cell science.

[44]  J. Swanson,et al.  A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages , 1996, The Journal of cell biology.

[45]  R. Klausner,et al.  Aluminum fluoride stimulates surface protrusions in cells overexpressing the ARF6 GTPase , 1996, The Journal of cell biology.

[46]  A. Dautry‐Varsat,et al.  The Staphylococcus aureus Enterotoxin B Superantigen Induces Specific T Cell Receptor Down-regulation by Increasing Its Internalization (*) , 1995, The Journal of Biological Chemistry.

[47]  C. D’Souza-Schorey,et al.  A regulatory role for ARF6 in receptor-mediated endocytosis , 1995, Science.

[48]  A. Ciechanover,et al.  pH and the recycling of transferrin during receptor-mediated endocytosis. , 1983, Proceedings of the National Academy of Sciences of the United States of America.