Interferon-Stimulated Genes: A Complex Web of Host Defenses

Abstract

Interferon-stimulated gene (ISG) products take on a number of diverse roles. Collectively, they are highly effective at resisting and controlling pathogens. In this review, we begin by introducing interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production. Next, we describe ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the JAK-STAT pathway. Several ISGs that directly inhibit virus infection are described with an emphasis on those that impact early and late stages of the virus life cycle. Finally, we describe ongoing efforts to identify and characterize antiviral ISGs, and we provide a forward-looking perspective on the ISG landscape.

Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

“…In response to this binding signal, the JAK‐STAT pathway is activated, leading to transcriptional up‐regulation of the ISGs (Ivashkiv & Donlin, 2014; Schneider et al , 2014). Therefore, to show that the up‐regulated ISGs upon HNRNPC knock‐down depend on the interferon signaling cascade, we used an IFNβ antibody, an IFNAR2 blocking antibody, and the JAK‐STAT inhibitor ruxolitinib to block the interferon signaling pathway at different levels.…”

“…IFNβ can be expressed in most of the cell types upon invasion of microbes and sensing of the microbial components by the pattern recognition receptors (PRRs; Nagarajan, 2011; Schneider et al , 2014). In addition, the type I interferon production can also be activated by the PRRs sensing the endogenous nucleic acids under stress conditions such as radiation, autoimmune disease, and cancer (West et al , 2015; Roers et al , 2016).…”

“…In addition, the type I interferon production can also be activated by the PRRs sensing the endogenous nucleic acids under stress conditions such as radiation, autoimmune disease, and cancer (West et al , 2015; Roers et al , 2016). Specifically, upon activation by their ligands, the cytoplasmic DNA sensors (ALR and cGAS) and RNA sensors (RIG‐I and MDA5) initiate the signaling cascade of interferon response (Honda et al , 2006; Goubau et al , 2013; Wu & Chen, 2014; McNab et al , 2015), leading to transcription of the ISGs (Platanias, 2005; Schneider et al , 2014). These interferon responses have been shown to be involved in regulating tumor development due to its well‐characterized pro‐apoptotic and anti‐proliferative effects in various types of cancer cells, including myeloma cell lines (Chen et al , 2001), lymphoma (Yang et al , 2013), liver cancer cells (Maeda et al , 2014; Murata et al , 2006; Sangfelt et al , 1997), and sarcoma cell lines (Sanceau et al , 2000).…”

Inactivation of the type I interferon pathway reveals long double‐stranded RNA‐mediated RNA interference in mammalian cells

“…In contrast, a recent study with human cells reported that activation of the IFN pathway through MAVS led to inhibition of RISC‐mediated cleavage and repression activities (Seo et al , 2013). Alternatively, the sequence‐specific hallmark of dsRNAi might be masked by sequence‐unspecific effects resulting from the activity of ISGs, which cause a dsRNA‐dependent shutdown in cellular protein synthesis and/or induce cell death (Samuel, 2001; Schneider et al , 2014). Irrespective of mechanism, our data suggest that RNAi might be especially important in conditions of limited IFN induction or in cellular niches that possess a reduced IFN response pathway.…”

“…In the IFN response, those RNAs are generally detected by members of the RIG‐I family of pattern recognition receptors, which then bind to the mitochondrial adaptor MAVS to initiate a signalling cascade that culminates in the production and secretion of IFN‐β and IFN‐α, among others (Goubau et al , 2013). IFN‐α and IFN‐β bind to the IFN receptor (IFNAR), which signals to induce hundreds of interferon‐stimulated genes (ISGs) that work to increase antiviral resistance (Samuel, 2001; Goubau et al , 2013; Schneider et al , 2014). For example, the ISG protein kinase R (PKR), when activated by viral dsRNA, phosphorylates the alpha subunit of the protein synthesis initiation factor‐2, causing inhibition of both viral and cellular translation (Pindel & Sadler, 2011).…”