Abstract
Recognition of microbial products by TLRs is critical for mediating innate immune responses to invading pathogens. In this study, we identify a novel scaffold protein in TLR4 signaling called SAM and SH3 domain containing protein 1 (SASH1). Sash1 is expressed across all microvascular beds and functions as a scaffold molecule to independently bind TRAF6, TAK1, IκB kinase α, and IκB kinase β. This interaction fosters ubiquitination of TRAF6 and TAK1 and promotes LPS-induced NF-κB, JNK, and p38 activation, culminating in increased production of proinflammatory cytokines and increased LPS-induced endothelial migration. Our findings suggest that SASH1 acts to assemble a signaling complex downstream of TLR4 to activate early endothelial responses to receptor activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Movement
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Endothelial Cells / metabolism*
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Enzyme Activation
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I-kappa B Kinase / metabolism
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Immunity, Innate
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lipopolysaccharides / immunology
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MAP Kinase Kinase Kinases / metabolism
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MAP Kinase Signaling System
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Mice
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Mice, Inbred C57BL
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NF-kappa B / metabolism
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RNA Interference
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Signal Transduction
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TNF Receptor-Associated Factor 6 / metabolism*
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Toll-Like Receptor 4 / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitination
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Lipopolysaccharides
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NF-kappa B
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Sash1 protein, mouse
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TNF Receptor-Associated Factor 6
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Tumor Suppressor Proteins
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Chuk protein, mouse
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I-kappa B Kinase
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7