title: Microbial sphingomyelinase induces RhoA-mediated reorganization of the apical brush border membrane and is protective against invasion.
abstract: The apical brush border membrane (BBM) of intestinal epithelial cells forms a highly structured and dynamic environmental interface that serves to regulate cellular physiology and block invasion by intestinal microbes and their products. How the BBM dynamically responds to pathogenic and commensal bacterial signals can define intestinal homeostasis and immune function. We previously found that in model intestinal epithelium, the conversion of apical membrane sphingomyelin to ceramide by exogenous bacterial sphingomyelinase (SMase) protected against the endocytosis and toxicity of cholera toxin. Here we elucidate a mechanism of action by showing that SMase induces a dramatic, reversible, RhoA-dependent alteration of the apical cortical F-actin network. Accumulation of apical membrane ceramide is necessary and sufficient to induce the actin phenotype, and this coincides with altered membrane structure and augmented innate immune function as evidenced by resistance to invasion by Salmonella.
authors: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA 02115 Harvard Digestive Diseases Center, Boston Children's Hospital, Boston, MA 02115 Harvard Medical School, Boston, MA 02115 david.saslowsky@nih.gov.
authors: David E
authors: DE
authors: Saslowsky
authors: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA 02115 Harvard Digestive Diseases Center, Boston Children's Hospital, Boston, MA 02115 Harvard Medical School, Boston, MA 02115.
authors: Jay R
authors: JR
authors: Thiagarajah
authors: Harvard Digestive Diseases Center, Boston Children's Hospital, Boston, MA 02115 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655.
authors: Beth A
authors: BA
authors: McCormick
authors: Harvard Medical School, Boston, MA 02115 Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
authors: Jean C
authors: JC
authors: Lee
authors: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA 02115 Harvard Digestive Diseases Center, Boston Children's Hospital, Boston, MA 02115 Harvard Medical School, Boston, MA 02115.
authors: Wayne I
authors: WI
authors: Lencer
mesh_terms: D008841:Actin Cytoskeleton / Q000276:immunology / Q000382:microbiology*; D000199:Actins; D001424:Bacterial Infections / Q000276:immunology / Q000378:metabolism; D002518:Ceramides / Q000096:biosynthesis; D006801:Humans; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D008871:Microvilli / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D012486:Salmonella typhimurium; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000201:enzymology; D020742:rhoA GTP-Binding Protein / Q000276:immunology*
chemical_list: D000199:Actins; D002518:Ceramides; D013108:Sphingomyelin Phosphodiesterase; D020742:rhoA GTP-Binding Protein