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.
Highlights
The ability of mammalian cells to distinguish self from nonself is paramount for triggering host immune defenses in response to viral infection
IFI16 is able to bind to the genomic DNA of several different nuclear replicating herpesviruses, including herpes simplex virus 1 (HSV-1) [8, 9, 11, 14, 18, 19] and human cytomegalovirus (HCMV) [13, 17], during infection and to coordinate the production of antiviral cytokines
HSV-1 Infection Triggers Proteasome-dependent Degradation of IFI16 —The ultimate goal of our study is to provide insights into the mechanisms by which IFI16 abates nuclear replicating herpesviruses, and the strategies herpesviruses use to impede IFI16-mediated functions
Summary
The ability of mammalian cells to distinguish self from nonself is paramount for triggering host immune defenses in response to viral infection. IFI16 is able to bind to the genomic DNA of several different nuclear replicating herpesviruses, including herpes simplex virus 1 (HSV-1) [8, 9, 11, 14, 18, 19] and human cytomegalovirus (HCMV) [13, 17], during infection and to coordinate the production of antiviral cytokines. These recent findings challenge the paradigm that DNA sensing is excluded from the nucleus to prevent superfluous immune activation by the host cell genome. The IFI16 protein interactions in the context of infection and the means through which it exerts its antiviral functions have not yet been characterized
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call