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Nat Immunol DOI:10.1038/ni.2509

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

Publication TypeJournal Article
Year of Publication2013
AuthorsLee, MN, Roy, M, Ong, S-E, Mertins, P, Villani, A-C, Li, W, Dotiwala, F, Sen, J, Doench, JG, Orzalli, MH, Kramnik, I, Knipe, DM, Lieberman, J, Carr, SA, Hacohen, N
JournalNat Immunol
Date Published2013 Feb
KeywordsAnimals, ATP-Binding Cassette Transporters, Cell Cycle Proteins, Chaperonins, Cytosol, Dendritic Cells, DNA, Viral, Fibroblasts, Gene Expression Regulation, Gene Silencing, HIV-1, HMGB2 Protein, HSP90 Heat-Shock Proteins, Humans, Immunity, Innate, Mice, Mice, Transgenic, Nuclear Proteins, Phosphoproteins, Protein-Serine-Threonine Kinases, Proteomics, RNA, Small Interfering, Signal Transduction, Small Molecule Libraries, Vesiculovirus

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.


Alternate JournalNat. Immunol.
PubMed ID23263557
PubMed Central IDPMC3838897
Grant ListAI102816 / AI / NIAID NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
HG005062 / HG / NHGRI NIH HHS / United States
DP2 OD002230 / OD / NIH HHS / United States
DP2OD002230 / OD / NIH HHS / United States
R01 AI102816 / AI / NIAID NIH HHS / United States
P01 HG005062 / HG / NHGRI NIH HHS / United States