Abstract
Members of the tripartite motif (TRIM) proteins are being recognized as important regulators of host innate immunity. However, specific TRIMs that contribute to TLR3-mediated antiviral defense have not been identified. We show here that TRIM56 is a positive regulator of TLR3 signaling. Overexpression of TRIM56 substantially potentiated extracellular dsRNA-induced expression of interferon (IFN)-β and interferon-stimulated genes (ISGs), while knockdown of TRIM56 greatly impaired activation of IRF3, induction of IFN-β and ISGs, and establishment of an antiviral state by TLR3 ligand and severely compromised TLR3-mediated chemokine induction following infection by hepatitis C virus. The ability to promote TLR3 signaling was independent of the E3 ubiquitin ligase activity of TRIM56. Rather, it correlated with a physical interaction between TRIM56 and TRIF. Deletion of the C-terminal portion of TRIM56 abrogated the TRIM56-TRIF interaction as well as the augmentation of TLR3-mediated IFN response. Together, our data demonstrate TRIM56 is an essential component of the TLR3 antiviral signaling pathway and reveal a novel role for TRIM56 in innate antiviral immunity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / immunology
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Adaptor Proteins, Vesicular Transport / metabolism
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Amino Acid Sequence
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HEK293 Cells
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HeLa Cells
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Hepacivirus / genetics
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Hepacivirus / immunology*
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Hepacivirus / metabolism
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Hepatitis C / genetics
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Hepatitis C / immunology*
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Hepatitis C / metabolism
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Humans
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Immunity, Innate*
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Interferon Regulatory Factor-3 / genetics
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Interferon Regulatory Factor-3 / immunology
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Interferon Regulatory Factor-3 / metabolism
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Interferon-beta / genetics
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Interferon-beta / immunology
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Interferon-beta / metabolism
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Sequence Deletion
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Toll-Like Receptor 3 / genetics
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Toll-Like Receptor 3 / immunology*
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Toll-Like Receptor 3 / metabolism
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Tripartite Motif Proteins
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / immunology*
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Ubiquitin-Protein Ligases / metabolism
Substances
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Adaptor Proteins, Vesicular Transport
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IRF3 protein, human
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Interferon Regulatory Factor-3
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TICAM1 protein, human
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TLR3 protein, human
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Toll-Like Receptor 3
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Tripartite Motif Proteins
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Interferon-beta
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TRIM56 protein, human
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Ubiquitin-Protein Ligases