Inactivation of Rho GTPases by Burkholderia cenocepacia Induces a WASH-Mediated Actin Polymerization that Delays Phagosome Maturation
Glenn F.W. Walpole,
Jonathan D. Plumb,
Daniel Chung,
Brandon Tang,
Benoit Boulay,
Douglas G. Osborne,
Joshua T. Piotrowski,
Sergio D. Catz,
Daniel D. Billadeau,
Sergio Grinstein,
Valentin Jaumouillé
Affiliations
Glenn F.W. Walpole
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
Jonathan D. Plumb
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Daniel Chung
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Brandon Tang
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Benoit Boulay
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Douglas G. Osborne
Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Joshua T. Piotrowski
Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Sergio D. Catz
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MB-215, La Jolla, CA 92037, USA
Daniel D. Billadeau
Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Sergio Grinstein
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Corresponding author
Valentin Jaumouillé
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Summary: Burkholderia cenocepacia is an opportunistic bacterial pathogen that causes severe pulmonary infections in cystic fibrosis and chronic granulomatous disease patients. B. cenocepacia can survive inside infected macrophages within the B. cenocepacia-containing vacuole (BcCV) and to elicit a severe inflammatory response. By inactivating the host macrophage Rho GTPases, the bacterial effector TecA causes depolymerization of the cortical actin cytoskeleton. In this study, we find that B. cenocepacia induces the formation of large cytosolic F-actin clusters in infected macrophages. Cluster formation requires the nucleation-promoting factor WASH, the Arp2/3 complex, and TecA. Inactivation of Rho GTPases by bacterial toxins is necessary and sufficient to induce the formation of the cytosolic actin clusters. By hijacking WASH and Arp2/3 activity, B. cenocepacia disrupts interactions with the endolysosomal system, thereby delaying the maturation of the BcCV.
