Title | Interactions of the Antiviral Factor Interferon Gamma-Inducible Protein 16 (IFI16) Mediate Immune Signaling and Herpes Simplex Virus-1 Immunosuppression. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Diner, BA, Lum, KK, Javitt, A, Cristea, IM |
Journal | Mol Cell Proteomics |
Volume | 14 |
Issue | 9 |
Pagination | 2341-56 |
Date Published | 2015 Sep |
ISSN | 1535-9484 |
Keywords | Cells, 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 | <p>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.</p> |
DOI | 10.1074/mcp.M114.047068 |
Alternate Journal | Mol Cell Proteomics |
PubMed ID | 25693804 |
PubMed Central ID | PMC4563720 |
Grant List | DP1 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 |