The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA

Benjamin A. Diner, Tuo Li, Todd M. Greco, Marni S. Crow, John A. Fuesler, Jennifer Wang, Ileana M. Cristea

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


The human PYHIN proteins, AIM2, IFI16, IFIX, and MNDA, are critical regulators of immune response, transcription, apoptosis, and cell cycle. However, their protein interactions and underlying mechanisms remain largely uncharacterized. Here, we provide the interaction network for all PYHIN proteins and define a function in sensing of viral DNA for the previously uncharacterized IFIX protein. By designing a cell-based inducible system and integrating microscopy, immunoaffinity capture, quantitative mass spectrometry, and bioinformatics, we identify over 300 PYHIN interactions reflective of diverse functions, including DNA damage response, transcription regulation, intracellular signaling, and antiviral response. In view of the IFIX interaction with antiviral factors, including nuclear PML bodies, we further characterize IFIX and demonstrate its function in restricting herpesvirus replication. We discover that IFIX detects viral DNA in both the nucleus and cytoplasm, binding foreign DNA via its HIN domain in a sequence-non-specific manner. Furthermore, IFIX contributes to the induction of interferon response. Our results highlight the value of integrative proteomics in deducing protein function and establish IFIX as an antiviral DNA sensor important for mounting immune responses.

Original languageEnglish (US)
Article number787
JournalMolecular Systems Biology
Issue number2
StatePublished - Feb 2015

All Science Journal Classification (ASJC) codes

  • General Immunology and Microbiology
  • Applied Mathematics
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


  • DNA sensing
  • IFIX
  • innate immunity
  • interactome


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