The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA
Autor: | Todd M. Greco, Benjamin A. Diner, Ileana M. Cristea, Tuo Li, Marni S. Crow, Jennifer Wang, John A. Fuesler |
---|---|
Rok vydání: | 2015 |
Předmět: |
Proteomics
Chromatin Immunoprecipitation DNA damage Antigens Differentiation Myelomonocytic interactome Herpesvirus 1 Human Computational biology Biology Interactome General Biochemistry Genetics and Molecular Biology Open Reading Frames AIM2 Transcription (biology) Databases Genetic Humans Immunologic Factors RNA Small Interfering innate immunity Cell Nucleus Genetics IFIX General Immunology and Microbiology IFI16 PYHIN Applied Mathematics MNDA Nuclear Proteins Sequence Analysis DNA Articles Cell cycle Phosphoproteins Recombinant Proteins DNA-Binding Proteins HEK293 Cells Computational Theory and Mathematics Multigene Family DNA Viral General Agricultural and Biological Sciences Signal Transduction Transcription Factors DNA sensing Information Systems |
Zdroj: | Molecular Systems Biology |
ISSN: | 1744-4292 |
DOI: | 10.15252/msb.20145808 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |