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

TitleThe functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA.
Publication TypeJournal Article
Year of Publication2015
AuthorsDiner, BA, Li, T, Greco, TM, Crow, MS, Fuesler, JA, Wang, J, Cristea, IM
JournalMol Syst Biol
Volume11
Issue1
Pagination787
Date Published2015 02 09
ISSN1744-4292
KeywordsAntigens, Differentiation, Myelomonocytic, Cell Nucleus, Chromatin Immunoprecipitation, Databases, Genetic, DNA, Viral, DNA-Binding Proteins, HEK293 Cells, Herpesvirus 1, Human, Humans, Immunologic Factors, Multigene Family, Nuclear Proteins, Open Reading Frames, Phosphoproteins, Proteomics, Recombinant Proteins, RNA, Small Interfering, Sequence Analysis, DNA, Signal Transduction, Transcription Factors
Abstract

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.

DOI10.15252/msb.20145808
Alternate JournalMol. Syst. Biol.
PubMed ID25665578
PubMed Central IDPMC4358659
Grant ListDP1DA026192 / DA / NIDA NIH HHS / United States
R01 GM114141 / GM / NIGMS NIH HHS / United States
R01 HL127640 / HL / NHLBI NIH HHS / United States
R21 AI102187 / AI / NIAID NIH HHS / United States
R21 HD073044 / HD / NICHD NIH HHS / United States
R21AI102187 / AI / NIAID NIH HHS / United States
R33 AI102187 / AI / NIAID NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States