New developments in the induction and antiviral effectors of type I interferon

Abstract

Type I interferons (IFNs) are cytokines of the innate immune system that induce antiviral protein expression in response to viral infection. Various proteins and pathways have been shown to recognize nucleic acid ligands especially from RNA viruses. Here, we will review recent developments including transcription of DNA virus genomes into RNA ligands, and the recognition of viruses by TLR2 for interferon induction. The induced IFNs activate many interferon stimulated genes (ISGs) that have direct antiviral effects. Recent studies have identified IFITM proteins as the first ISG to inhibit viral entry processes and revealed mechanistic understanding of known antiviral ISGs such as ISG15 and Viperin.

Figure 1. Old and New Players in the Induction of IFN

TANK-binding kinase-1 (TBK1) is the primary IRF3 activating kinase. IRF3 is activated by phosphorylation, after which is translocates to the nucleus and induce Interferon gene transcription. DNA induction of this pathway may occur by RNA Polymerase III (RNAP3) transcription of abundant DNA into RNA, which can then function as a RIG-I substrate. RIG-I is well known in RNA induction pathways to signal through CARDIF, a mitochondrial adaptor to TRAF3 and downstream to TBK1. In addition, DAI has been found to recognize DNA and induce signals downstream to TBK1. Further studies may reveal new receptors that are either parallel or a more primary receptor for DNA that either DAI or RNAP3. However, STING has recently been found to be an ER associated multi-membrane protein that is required for signaling by these nucleic acid receptors, potentially by serving as a signaling docking and coordination center. In addition, TLR2 has recently been found to induce IRF3 activation in inflammatory monocytes by signaling from endosomal compartments. Finally, LRRFIP1 has recently been found to respond to cytoplasmic nucleic acids and signal to induce β-catenin phosphorylation. Phosphorylated β-catenin translocate to the nucleus and is recruited to interferon promoters to activate CBP/p300 that then induce acetylation and activation of the interferon promoter in a mechanism whose importance is still being dissected.

Figure 2. General Anti-viral Mechanisms of Interferon Stimulated Genes

The general lifecycle stages of an enveloped virus are depicted here (light blue letters). The virus binds to specific receptors on the cell surface and often enters the cell through endocytosis. Viral genetic material is released into the cytoplasm through pH-dependent or -independent fusion and may be subsequently transported to the nucleus. Replication of viral genetic material ensues along with mRNA transcription followed by transport to the ER for protein translation. Envelope proteins are transported to the cell surface while core viral proteins assemble with the viral genetic material. New virion particles are enveloped as they bud out of the plasma membrane. ISGs (in capital black bold letters) can inhibit viruses differently and at one or more stages of the viral lifecycle, see Table 1.