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

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.

SUBMITTER: Lee MN 

PROVIDER: S-EPMC3838897 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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

Lee Mark N MN   Roy Matthew M   Ong Shao-En SE   Mertins Philipp P   Villani Alexandra-Chloé AC   Li Weibo W   Dotiwala Farokh F   Sen Jayita J   Doench John G JG   Orzalli Megan H MH   Kramnik Igor I   Knipe David M DM   Lieberman Judy J   Carr Steven A SA   Hacohen Nir N  

Nature immunology 20121223 2

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  ...[more]

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