Induction of type I interferon by RNA viruses: cellular receptors and their substrates

Baum, Alina; García-Sastre, Adolfo

To date, two distinct systems for RNA virus detection and interferon induction have been characterized. One is composed of toll-like receptors (TLRs) and the other is the RIG-I like receptor (RLR) family. Of the 13 mammalian TLR members identified to date, endosomally located TLR3, TLR7 and TLR8 have been characterized as principal sensors of RNA viruses, while other TLRs are responsible for detecting bacteria, fungi, and DNA viruses (Alexopoulou et al. 2001; Diebold et al. 2004) . Extracellularly located TLR4 has also been implicated in RNA virus detection through recognition of the F protein of respiratory syncytial virus (Kurt-Jones et al. 2000) . RIG-I and MDA5, of the RLR family, are cytoplasmic sensors expressed in majority of cell types and detect intracellular RNA viruses. Viral RNA is thought to function as the pathogen-associated molecular pattern (PAMP) for all intracellular RNA virus pattern-recognition receptors (PRRs), although the exact biochemical nature of inducing molecules remains unclear. Current understanding indicates that TLR3 recognizes any dsRNA in endocytic compartments while MDA5 recognizes long dsRNA in the cytoplasm, TLR7 and 8 are activated by ssRNA rich in G/U residues in endosomes of dendritic cells and RIG-I senses phosphate containing dsRNA in the cytoplasm of majority of cells (Table 1) . Upon detection of their corresponding PAMPs, both TLRs and RLRs initiate signaling cascades which converge on activation, and subsequent nuclear localization of three families of transcription factors: NF-jB, interferon regulatory factors (IRFs), and ATF-2/cJun. As can be seen in Fig. 1 , the signaling pathways for TLR3 and RLRs utilize adaptors TRIF and MAVS, respectively, and then converge with activation of the canonical (IKKa, b, and c) and noncanonical (TBK1, IKKe) IKK kinases. Activation of TBK1/ IKKe leads to phosphorylation and nuclear translocation of IRF3. Whereas IKKa, b, and c activate and allow nuclear translocation of NF-jB. TLR7 and 8 in dendritic cells utilize a common TLR adaptor MyD88 to activate a complex of IRAK4/IRAK1/TRAF6, which in turn lead to phosphorylation and nuclear translocation of IRF7. These signaling cascades results in transcription of IFN-b or IFNa genes and production of the first wave of type I interferon (Thompson and Locarnini 2007) . Following synthesis, IFN is secreted from the infected cell and initiates an autocrine and paracrine-signaling cascade through Type I IFN receptor (IFNAR) which results in upregulation of more than 100 different genes and creation of an antiviral state in both infected and neighboring uninfected cells. Although the functions of the majority of IFN stimulated genes are not known, some are well characterized and are involved in inhibition of the viral lifecycle by shutting down general cellular processes (Samuel 2001) . In addition to its antiviral function, IFN has also been shown to play an important role in modulation of the adaptive immune response through stimulation of MHC class I presentation, activation of natural killer (NK) cells and cytotoxic T cells, and maturation of dendritic cells (DCs) (Biron 2001; Le Bon and Tough 2002; Stetson and Medzhitov 2006) .