Thioredoxin-interacting protein mediates TRX1 translocation to the plasma membrane in response to tumor necrosis factor-α: a key mechanism for vascular endothelial growth factor receptor-2 transactivation by reactive oxygen species.
Thioredoxin-interacting protein (TXNIP) promotes inflammation in endothelial cells (EC) by binding to thioredoxin-1 (TRX1) in a redox-dependent manner. Formation of the TXNIP-TRX1 complex relieves inhibition of the apoptosis signal-regulating kinase 1-c-Jun N-terminal kinase-vascular cell adhesion molecule-1 pathway. Because TXNIP is an α-arrestin with numerous protein-protein interacting domains, we hypothesized that ... TXNIP-TRX1 trafficking should alter function of EC exposed to reactive oxygen species (ROS).In response to physiological levels of ROS (10 ng/mL tumor necrosis factor-α and 30 μmol/L H(2)O(2)), TXNIP-TRX1 translocated to the plasma membrane in human umbilical vein EC, with a peak at 30 minutes, as measured by immunofluorescence colocalization with vascular endothelial-cadherin, cell fractionation, and membrane sheet assay. TXNIP-mediated translocation of TRX1 to the membrane required TXNIP and TRX1 binding, as evidenced by inability of the ROS-insensitive TXNIP-Cys247Ser mutant to promote membrane localization. Vascular endothelial growth factor signaling required TXNIP, as shown by significant decreases in plasma membrane tyrosine phosphorylation and EC migration after TRX1 knockdown. Furthermore, TXNIP knockdown increased human umbilical vein EC apoptosis induced by tumor necrosis factor. Rescue with TXNIP-wild-type but not TXNIP-Cys247Ser prevented cell death.These findings suggest a novel role for the TXNIP-TRX1 complex to enable inflammation by promoting EC survival and vascular endothelial growth factor signaling under conditions of physiological oxidative stress.
Mesh Terms:
Amino Acid Substitution, Base Sequence, Carrier Proteins, Cell Movement, Cell Survival, Cells, Cultured, Endothelial Cells, Gene Knockdown Techniques, Humans, Mutagenesis, Site-Directed, Oxidation-Reduction, Phosphorylation, Protein Interaction Domains and Motifs, Protein Transport, RNA, Small Interfering, Reactive Oxygen Species, Recombinant Proteins, Signal Transduction, Thioredoxins, Transcriptional Activation, Tumor Necrosis Factor-alpha, Tyrosine, Vascular Endothelial Growth Factor Receptor-2
Amino Acid Substitution, Base Sequence, Carrier Proteins, Cell Movement, Cell Survival, Cells, Cultured, Endothelial Cells, Gene Knockdown Techniques, Humans, Mutagenesis, Site-Directed, Oxidation-Reduction, Phosphorylation, Protein Interaction Domains and Motifs, Protein Transport, RNA, Small Interfering, Reactive Oxygen Species, Recombinant Proteins, Signal Transduction, Thioredoxins, Transcriptional Activation, Tumor Necrosis Factor-alpha, Tyrosine, Vascular Endothelial Growth Factor Receptor-2
Arterioscler. Thromb. Vasc. Biol.
Date: Aug. 01, 2011
PubMed ID: 21636804
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