GTPase activating protein function of p85 facilitates uptake and recycling of the beta1 integrin.
Beta1-containing adhesions at the plasma membrane function as dynamic complexes to provide bidirectional communication between the cell and its environment, yet commonly are used by pathogens to gain host cell entry. Recently, the cholesterol-lowering drug simvastatin was found to inhibit host invasion through beta1-containing adhesion complexes. To better understand the regulatory mechanisms controlling adhesion formation and uptake and the use of these complexes by Staphylococcus aureus, the primary etiologic agent in sepsis, bacteremia and endocarditis, we investigated the mechanism of inhibition by simvastatin. In response to simvastatin, adhesion complexes diminished as well as beta1 trafficking to the plasma membrane required to initiate adhesion formation. Simvastatin stimulated CDC42 activation and coupling to p85, a small-guanosine triphosphatase (GTPase) activating protein (GAP), yet sequestered CDC42 coupled to p85 within the cytosol. Loss of p85 GAP activity through use of genetic strategies decreased host cell invasion as well as beta1 trafficking. From these findings, we propose a mechanism whereby p85 GAP activity localized within membrane compartments facilitates beta1 trafficking. By sequestering p85 within the cytosol, simvastatin restricts the availability and uptake of the receptor used by pathogenic strains to gain host cell entry.
Stankiewicz
Traci E
TE
Ball State University, Muncie, IN 47306, USA.
Haaning
Kelsey L
KL
Owens
Janelle M
JM
Jordan
Alys S
AS
Gammon
Kelly
K
Bruns
Heather A
HA
McDowell
Susan A
SA
D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000201:enzymology* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000472:pathogenicity*; D041701:Swiss 3T3 Cells; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019012:Integrin beta1; D019821:Simvastatin; D019869:Phosphatidylinositol 3-Kinases; D020764:cdc42 GTP-Binding Protein