Abstract
We have previously shown that mutations of CD14 or TLR4 impair type I interferon (IFN) production and macrophage survival during infection with vesicular stomatitis virus (VSV). We now report that VSV glycoprotein G (gpG) is essential for the induction of a previously unrecognized CD14/TLR4-dependent response pathway in which the adapter TRAM has predominant importance, absent any need for MyD88 or Mal, and with only a partial requirement for TRIF. Downstream of TRAM, IRF7 activation leads to a type I IFN response. The pathway is utilized by myeloid dendritic cells (mDCs) and macrophages rather than plasmacytoid DCs. This new mode of TLR4 signal transduction, which does not stimulate NF-kappaB activation, reveals the importance of viral protein recognition by mDCs and shows that TLR4 can drive qualitatively different events within the cell in response to different ligands.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / immunology
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Animals
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Cell Line
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Cell Survival
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Dendritic Cells / immunology
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Female
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Gene Expression Regulation
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Humans
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Interferon Regulatory Factor-7 / biosynthesis
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Interferon Type I / biosynthesis
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Macrophages, Peritoneal / virology
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Male
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Membrane Glycoproteins / immunology*
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Membrane Transport Proteins / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Animal
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Myelin Proteins / immunology
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Myelin and Lymphocyte-Associated Proteolipid Proteins
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Myeloid Differentiation Factor 88 / immunology
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Proteolipids / immunology
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RNA, Messenger / biosynthesis
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Receptors, Interleukin / immunology
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Signal Transduction*
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Toll-Like Receptor 4 / immunology*
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Toll-Like Receptor 4 / metabolism
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Vesicular stomatitis Indiana virus / immunology*
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Viral Envelope Proteins / immunology*
Substances
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Adaptor Proteins, Vesicular Transport
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G protein, vesicular stomatitis virus
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Interferon Regulatory Factor-7
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Interferon Type I
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Irf7 protein, mouse
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MAL protein, human
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Mal protein, mouse
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Membrane Glycoproteins
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Membrane Transport Proteins
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Myd88 protein, mouse
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Myelin Proteins
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Myelin and Lymphocyte-Associated Proteolipid Proteins
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Myeloid Differentiation Factor 88
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Proteolipids
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RNA, Messenger
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Receptors, Interleukin
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TICAM-1 protein, mouse
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Ticam2 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Viral Envelope Proteins