Interactions of the Antiviral Factor Interferon Gamma-Inducible Protein 16 (IFI16) Mediate Immune Signaling and Herpes Simplex Virus-1 Immunosuppression.

TitleInteractions of the Antiviral Factor Interferon Gamma-Inducible Protein 16 (IFI16) Mediate Immune Signaling and Herpes Simplex Virus-1 Immunosuppression.
Publication TypeJournal Article
Year of Publication2015
AuthorsDiner, BA, Lum, KK, Javitt, A, Cristea, IM
JournalMol Cell Proteomics
Volume14
Issue9
Pagination2341-56
Date Published2015 09 01
ISSN1535-9484
KeywordsCells, Cultured, Cytokines, DNA, Viral, DNA-Binding Proteins, Gene Expression Regulation, HEK293 Cells, Herpes Simplex, Herpesvirus 1, Human, Humans, Immediate-Early Proteins, Nuclear Proteins, Phosphoproteins, Proteolysis, Proteomics, Signal Transduction, Ubiquitin-Protein Ligases, Viral Proteins
Abstract

The interferon-inducible protein IFI16 has emerged as a critical antiviral factor and sensor of viral DNA. IFI16 binds nuclear viral DNA, triggering expression of antiviral cytokines during infection with herpesviruses. The knowledge of the mechanisms and protein interactions through which IFI16 exerts its antiviral functions remains limited. Here, we provide the first characterization of endogenous IFI16 interactions following infection with the prominent human pathogen herpes simplex virus 1 (HSV-1). By integrating proteomics and virology approaches, we identified and validated IFI16 interactions with both viral and host proteins that are involved in HSV-1 immunosuppressive mechanisms and host antiviral responses. We discover that during early HSV-1 infection, IFI16 is recruited to sub-nuclear puncta and subsequently targeted for degradation. We observed that the HSV-1 E3 ubiquitin ligase ICP0 is necessary, but not sufficient, for the proteasom e-mediated degradation of IFI16 following infection. We substantiate that this ICP0-mediated mechanism suppresses IFI16-dependent immune responses. Utilizing an HSV-1 strain that lacks ICP0 ubiquitin ligase activity provided a system for studying IFI16-dependent cytokine responses to HSV-1, as IFI16 levels were maintained throughout infection. We next defined temporal IFI16 interactions during this immune signaling response. We discovered and validated interactions with the viral protein ICP8 and cellular ND10 nuclear body components, sites at which HSV-1 DNA is present during infection. These interactions may be critical for IFI16 to bind to nuclear viral DNA. Altogether, our results provide critical insights into both viral inhibition of IFI16 and interactions that can contribute to IFI16 antiviral functions.

DOI10.1074/mcp.M114.047068
Alternate JournalMol. Cell Proteomics
PubMed ID25693804
PubMed Central IDPMC4563720
Grant ListDP1 DA026192 / DA / NIDA NIH HHS / United States
R21HD073044 / HD / NICHD NIH HHS / United States
DP1DA026192 / DA / NIDA NIH HHS / United States
R21 AI102187 / AI / NIAID NIH HHS / United States
R01 GM114141 / GM / NIGMS NIH HHS / United States
R01 HL127640 / HL / NHLBI NIH HHS / United States
R33 AI102187 / AI / NIAID NIH HHS / United States
R21 HD073044 / HD / NICHD NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R21AI102187 / AI / NIAID NIH HHS / United States