A Tug of War: DNA-Sensing Antiviral Innate Immunity and Herpes Simplex Virus Type I Infection

Rapid induction of type I interferon expression, a central event in establishing the innate antiviral response, requires cooperative activation of numerous transcription factors. Although signaling pathways that activate the transcription factors nuclear factor kappaB and ATF-2/c-Jun have been well characterized, activation of the interferon regulatory factors IRF-3 and IRF-7 has remained a critical missing link in understanding interferon signaling. We report here that the IkappaB kinase (IKK)-related kinases IKKepsilon and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7. These studies illustrate an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection.

In the absence of an intact interferon (IFN) response, mammals may be susceptible to lethal viral infection. IFNs are secreted cytokines that activate a signal transduction cascade leading to the induction of hundreds of interferon-stimulated genes (ISGs). Remarkably, approximately 10% of the genes in the human genome have the potential to be regulated by IFNs. What do all of these genes do? It is a complex question without a simple answer. From decades of research, we know that many of the protein products encoded by these ISGs work alone or in concert to achieve one or more cellular outcomes, including cell intrinsic antiviral defense, antiproliferative activities, and stimulation of adaptive immunity. The focus of this review is the antiviral activities of the IFN/ISG system. This includes general paradigms of ISG function, supported by specific examples in the literature, as well as methodologies to identify and characterize ISG function. Expected final online publication date for the Annual Review of Virology Volume 6 is September 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Microbial nucleic acids are critical for the induction of innate immune responses, a host defense mechanism against infection by microbes. Recent studies have indicated that double-stranded DNA (dsDNA) induces potent innate immune responses via the induction of type I IFN (IFN) and IFN-inducible genes. However, the regulatory mechanisms underlying dsDNA-triggered signaling are not fully understood. Here we show that the translocation and assembly of the essential signal transducers, stimulator of IFN genes (STING) and TANK-binding kinase 1 (TBK1), are required for dsDNA-triggered innate immune responses. After sensing dsDNA, STING moves from the endoplasmic reticulum (ER) to the Golgi apparatus and finally reaches the cytoplasmic punctate structures to assemble with TBK1. The addition of an ER-retention signal to the C terminus of STING dampens its ability to induce antiviral responses. We also show that STING co-localizes with the autophagy proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related gene 9a (Atg9a), after dsDNA stimulation. The loss of Atg9a, but not that of another autophagy-related gene (Atg7), greatly enhances the assembly of STING and TBK1 by dsDNA, leading to aberrant activation of the innate immune response. Hence Atg9a functions as a regulator of innate immunity following dsDNA stimulation as well as an essential autophagy protein. These results demonstrate that dynamic membrane traffic mediates the sequential translocation and assembly of STING, both of which are essential processes required for maximal activation of the innate immune response triggered by dsDNA.