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

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 a...

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Autores principales: Diner, Benjamin A, Li, Tuo, Greco, Todd M, Crow, Marni S, Fuesler, John A, Wang, Jennifer, Cristea, Ileana M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358659/
https://www.ncbi.nlm.nih.gov/pubmed/25665578
http://dx.doi.org/10.15252/msb.20145808
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author Diner, Benjamin A
Li, Tuo
Greco, Todd M
Crow, Marni S
Fuesler, John A
Wang, Jennifer
Cristea, Ileana M
author_facet Diner, Benjamin A
Li, Tuo
Greco, Todd M
Crow, Marni S
Fuesler, John A
Wang, Jennifer
Cristea, Ileana M
author_sort Diner, Benjamin A
collection PubMed
description 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.
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spelling pubmed-43586592015-03-20 The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA Diner, Benjamin A Li, Tuo Greco, Todd M Crow, Marni S Fuesler, John A Wang, Jennifer Cristea, Ileana M Mol Syst Biol Articles 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. BlackWell Publishing Ltd 2015-02-09 /pmc/articles/PMC4358659/ /pubmed/25665578 http://dx.doi.org/10.15252/msb.20145808 Text en © 2015 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Diner, Benjamin A
Li, Tuo
Greco, Todd M
Crow, Marni S
Fuesler, John A
Wang, Jennifer
Cristea, Ileana M
The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA
title The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA
title_full The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA
title_fullStr The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA
title_full_unstemmed The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA
title_short The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA
title_sort functional interactome of pyhin immune regulators reveals ifix is a sensor of viral dna
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358659/
https://www.ncbi.nlm.nih.gov/pubmed/25665578
http://dx.doi.org/10.15252/msb.20145808
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