Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach
Copyright policy )Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach
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.
- Boston Children's Hospital United States
- Harvard University United States
- University of Washington United States
- Boston College United States
- Broad Institute United States
Chaperonins, Nuclear Proteins, Cell Cycle Proteins, Mice, Transgenic, Dendritic Cells, Fibroblasts, Protein Serine-Threonine Kinases, Phosphoproteins, Immunity, Innate, Mice, Cytosol, Gene Expression Regulation, DNA, Viral, HIV-1, Animals, HMGB2 Protein, Humans, ATP-Binding Cassette Transporters, Gene Silencing, HSP90 Heat-Shock Proteins
Chaperonins, Nuclear Proteins, Cell Cycle Proteins, Mice, Transgenic, Dendritic Cells, Fibroblasts, Protein Serine-Threonine Kinases, Phosphoproteins, Immunity, Innate, Mice, Cytosol, Gene Expression Regulation, DNA, Viral, HIV-1, Animals, HMGB2 Protein, Humans, ATP-Binding Cassette Transporters, Gene Silencing, HSP90 Heat-Shock Proteins
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