CGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

Megan H. Orzalli, Nicole M. Broekema, Benjamin A. Diner, Dustin C. Hancks, Nels C. Elde, Ileana M. Cristea, David M. Knipe

Research output: Contribution to journalArticlepeer-review

195 Scopus citations


Interferon γ-inducible protein 16 (IFI16) and cGMP-AMP synthase (cGAS) have both been proposed to detect herpesviral DNA directly in herpes simplex virus (HSV)-infected cells and initiate interferon regulatory factor-3 signaling, but it has been unclear how two DNA sensors could both be required for this response. We therefore investigated their relative roles in human foreskin fibroblasts (HFFs) infected with HSV or transfected with plasmid DNA. siRNA depletion studies showed that both are required for the production of IFN in infected HFFs. We found that cGAS shows low production of cGMP-AMP in infected cells, but instead cGAS is partially nuclear in normal human fibroblasts and keratinocytes, interacts with IFI16 in fibroblasts, and promotes the stability of IFI16. IFI16 is associated with viral DNA and targets to viral genome complexes, consistent with it interacting directly with viral DNA. Our results demonstrate that IFI16 and cGAS cooperate in a novel way to sense nuclear herpesviral DNA and initiate innate signaling. protein-protein interactions, DNA sensing, innate immunity, virus-host interactions.

Original languageEnglish (US)
Pages (from-to)E1773-E1781
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
StatePublished - Apr 7 2015

All Science Journal Classification (ASJC) codes

  • General


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