Cytosolic Sensing of Viruses

Abstract

Cells are equipped with mechanisms that allow them to rapidly detect and respond to viruses. These defense mechanisms rely partly on receptors that monitor the cytosol for the presence of atypical nucleic acids associated with virus infection. RIG-I-like receptors detect RNA molecules that are absent from the uninfected host. DNA receptors alert the cell to the abnormal presence of that nucleic acid in the cytosol. Signaling by RNA and DNA receptors results in the induction of restriction factors that prevent virus replication and establish cell-intrinsic antiviral immunity. In light of these formidable obstacles, viruses have evolved mechanisms of evasion, masking nucleic acid structures recognized by the host, sequestering themselves away from the cytosol or targeting host sensors, and signaling adaptors for deactivation or degradation. Here, we detail recent advances in the molecular understanding of cytosolic nucleic acid detection and its evasion by viruses.

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

“…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).…”

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

“…In mammals, the type I interferon (IFN) response constitutes an effective means to halt viral intruders. This innate immune response is initiated by the recognition of virally derived nucleic acids within the host cells by a dedicated group of receptors, which signal to induce a transcriptional response resulting in the production and secretion of type I IFNs (mainly IFN‐α and IFN‐β; Goubau et al , 2013; Schneider et al , 2014; Wu & Chen, 2014; Schlee & Hartmann, 2016). These key antiviral cytokines signal in an autocrine and paracrine fashion via the type I interferon receptor (IFNAR) to induce the expression of hundreds of interferon‐stimulated genes (ISGs) that encode proteins that inhibit viral replication and dissemination (Goubau et al , 2013; Schneider et al , 2014).…”

“…This family of DExH/D helicases encompasses RIG‐I (retinoic acid‐inducible gene I), MDA5 (melanoma differentiation‐associated gene 5) and LGP2 (laboratory of genetics and physiology 2; Goubau et al , 2013; Wu & Chen, 2014; Schlee & Hartmann, 2016). RIG‐I and MDA5 share a similar domain organisation.…”

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

“…Instead, infection of vertebrate cells with viruses triggers the innate interferon (IFN) response, a vertebrate‐restricted system of antiviral defence that can be elicited by the same ds and base‐paired RNAs that serve as Dicer substrates. 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).…”

“…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).…”