Abstract
The innate immune system senses viral DNA that enters mammalian cells, or in aberrant situations self-DNA, and triggers type I interferon production. Here we present an integrative approach that combines quantitative proteomics, genomics and small molecule perturbations to identify genes involved in this pathway. We silenced 809 candidate genes, measured the response to dsDNA and connected resulting hits with the known signaling network. We identified ABCF1 as a critical protein that associates with dsDNA and the DNA-sensing components HMGB2 and IFI204. We also found that CDC37 regulates the stability of the signaling molecule TBK1 and that chemical inhibition of the CDC37-HSP90 interaction and several other pathway regulators potently modulates the innate immune response to DNA and retroviral infection.
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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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / immunology*
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Animals
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / immunology
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Chaperonins / antagonists & inhibitors
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Chaperonins / genetics
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Chaperonins / immunology
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Cytosol / drug effects
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Cytosol / metabolism
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Cytosol / virology
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DNA, Viral / genetics
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DNA, Viral / immunology*
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Dendritic Cells / virology
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Fibroblasts / drug effects
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Fibroblasts / immunology*
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Fibroblasts / virology
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / immunology
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Gene Silencing
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HIV-1 / physiology
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HMGB2 Protein / genetics
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HMGB2 Protein / immunology
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / immunology
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Humans
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Immunity, Innate*
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Mice
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Mice, Transgenic
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology
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Phosphoproteins / genetics
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Phosphoproteins / immunology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Proteomics
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Small Molecule Libraries / pharmacology
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Vesiculovirus / physiology
Substances
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ABCF1 protein, human
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ATP-Binding Cassette Transporters
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CDC37 protein, human
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Cell Cycle Proteins
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DNA, Viral
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HMGB2 Protein
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HSP90 Heat-Shock Proteins
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Ifi16 protein, mouse
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Nuclear Proteins
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Phosphoproteins
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RNA, Small Interfering
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Small Molecule Libraries
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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Chaperonins
Associated data
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GEO/GSE42802
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GEO/GSE42803