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Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach

Item Type:Article
Title:Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach
Creators Name:Lee, M.N. and Roy, M. and Ong, S.E. and Mertins, P. and Villani, A.C. and Li, W. and Dotiwala, F. and Sen, J. and Doench, J.G. and Orzalli, M.H. and Kramnik, I. and Knipe, D.M. and Lieberman, J. and Carr, S.A. and Hacohen, N.
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-ensing 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.
Keywords:ATP-Binding Cassette Transporters, Cell Cycle Proteins, Chaperonins, Cytosol, Dendritic Cells, Fibroblasts, Gene Expression Regulation, Gene Silencing, HIV-1, HMGB2 Protein, HSP90 Heat-Shock Proteins, Innate Immunity, Nuclear Proteins, Phosphoproteins, Protein-Serine-Threonine Kinases, Proteomics, Signal Transduction, Small Interfering RNA, Small Molecule Libraries, Transgenic Mice, Vesiculovirus, Viral DNA, Animals, Mice
Source:Nature Immunology
ISSN:1529-2908
Publisher:Nature Publishing Group (U.S.A.)
Volume:14
Number:2
Page Range:179-185
Date:February 2013
Official Publication:https://doi.org/10.1038/ni.2509
PubMed:View item in PubMed

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