TY - JOUR
T1 - MYADM controls endothelial barrier function through ERM-dependent regulation of ICAM-1 expression
AU - Aranda, Juan F.
AU - Reglero-Real, Natalia
AU - Marcos-Ramiro, Beatriz
AU - Ruiz-Saenz, Ana
AU - Fernandez-Martin, Laura
AU - Bernabe-Rubio, Miguel
AU - Kremer, Leonor
AU - Ridley, Anne J.
AU - Correas, Isabel
AU - Alonso, Miguel A.
AU - Millan, Jaime
PY - 2013/2/15
Y1 - 2013/2/15
N2 - 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-a. MYADM therefore regulates the connection between the plasma membrane and the cortical cytoskeleton and so can control the endothelial inflammatory response.
AB - 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-a. MYADM therefore regulates the connection between the plasma membrane and the cortical cytoskeleton and so can control the endothelial inflammatory response.
KW - KAPPA-B ACTIVATION
KW - HUMAN T-LYMPHOCYTES
KW - LIPID RAFTS
KW - EZRIN/RADIXIN/MOESIN PROTEINS
KW - TNF-ALPHA
KW - PLASMA-MEMBRANE
KW - MAL PROTEIN
KW - CYTOSKELETAL REORGANIZATION
KW - VASCULAR-PERMEABILITY
KW - ADHERENS JUNCTIONS
U2 - 10.1091/mbc.E11-11-0914
DO - 10.1091/mbc.E11-11-0914
M3 - Article
SN - 1059-1524
VL - 24
SP - 483
EP - 494
JO - Mol Biol Cell
JF - Mol Biol Cell
IS - 4
M1 - N/A
ER -