title: MYADM controls endothelial barrier function through ERM-dependent regulation of ICAM-1 expression.
abstract: The endothelium maintains a barrier between blood and tissue that becomes more permeable during inflammation. Membrane rafts are ordered assemblies of cholesterol, glycolipids, and proteins that modulate proinflammatory cell signaling and barrier function. In epithelial cells, the MAL family members MAL, MAL2, and myeloid-associated differentiation marker (MYADM) regulate the function and dynamics of ordered membrane domains. We analyzed the expression of these three proteins in human endothelial cells and found that only MYADM is expressed. MYADM was confined in ordered domains at the plasma membrane, where it partially colocalized with filamentous actin and cell-cell junctions. Small interfering RNA (siRNA)-mediated MYADM knockdown increased permeability, ICAM-1 expression, and leukocyte adhesion, all of which are features of an inflammatory response. Barrier function decrease in MYADM-silenced cells was dependent on ICAM-1 expression. Membrane domains and the underlying actin cytoskeleton can regulate each other and are connected by ezrin, radixin, and moesin (ERM) proteins. In endothelial cells, MYADM knockdown induced ERM activation. Triple-ERM knockdown partially inhibited ICAM-1 increase induced by MYADM siRNA. Importantly, ERM knockdown also reduced ICAM-1 expression in response to the proinflammatory cytokine tumor necrosis factor-α. MYADM therefore regulates the connection between the plasma membrane and the cortical cytoskeleton and so can control the endothelial inflammatory response.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Aranda
authors.forename: Natalia
authors.initials: N
authors.lastname: Reglero-Real
authors.forename: Beatriz
authors.initials: B
authors.lastname: Marcos-Ramiro
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Sáenz
authors.forename: Laura
authors.initials: L
authors.lastname: Fernández-Martín
authors.forename: Miguel
authors.initials: M
authors.lastname: Bernabé-Rubio
authors.forename: Leonor
authors.initials: L
authors.lastname: Kremer
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Ridley
authors.forename: Isabel
authors.initials: I
authors.lastname: Correas
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Alonso
authors.forename: Jaime
authors.initials: J
authors.lastname: Millán
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D018799:Intercellular Adhesion Molecule-1; D008565:Membrane Proteins; D008840:Microfilament Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000099149:Ezrin; C405987:MYADM protein, human; C071058:moesin; C071776:radixin