Innate Immunity Minireview Series: Making Biochemical Sense of Nucleic Acid Sensors That Trigger Antiviral Innate Immunity

An important component of the innate immune response of the host in viral infection is the production of type I interferons. Efforts to understand the molecular mechanisms by which animal viruses and also double-stranded RNA trigger the induction of interferon (IFN) 2The abbreviations used are: IFN, interferon; dsRNA, double-stranded RNA; IRF, interferon regulatory factor; IPS-1, interferon promoter stimulator 1; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; RIG-I, retinoic acid inducible gene I; RLR, RIG-I-like receptor; ssRNA, single-stranded RNA; TLR, Toll-like receptor; TRIF, Toll/interleukin 1 receptor domain-containing adaptor protein inducing interferon.2The abbreviations used are: IFN, interferon; dsRNA, double-stranded RNA; IRF, interferon regulatory factor; IPS-1, interferon promoter stimulator 1; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; RIG-I, retinoic acid inducible gene I; RLR, RIG-I-like receptor; ssRNA, single-stranded RNA; TLR, Toll-like receptor; TRIF, Toll/interleukin 1 receptor domain-containing adaptor protein inducing interferon. have led to the identification of cellular sensors of viral infection. The first two minireviews in this issue provide updates on two kinds of nucleic acid sensors and the biochemical pathways by which they signal the production of interferon. One type of sensor is the family of cytosolic receptor proteins (RIG-I, MDA5, LGP2) known as the retinoic acid-inducible gene I (RIG-I)-like receptors (RLR). The other type of sensor includes members of the Toll-like receptor (TLR) family of cell surface and endosomal membrane protein receptors (TLR3, -7, -8, and -9). These minireviews focus on the biochemical and cellular aspects of the signaling pathways activated by RNA, both single-stranded (ss) RNA and double-stranded (ds) RNA, including the nature of the RLR and TLR sensor proteins and the adaptors through which they signal the production of IFN in virus-infected cells. The third minireview focuses on the structure and function of interferon regulatory factor (IRF) 3 and, to an extent, IRF-7, which are activated by the RLR and TLR signaling pathways. These IRFs, together with the nuclear factor-κB (NF-κB) and activator protein 1 factors lead to the transcriptional activation of the type I interferon β (IFN-β) gene.Interferon was discovered as an antiviral cytokine 50 years ago during seminal studies on virus interference (1Isaacs A. Lindenmann J. Proc. R. Soc. Lond. Ser. B Biol. Sci. 1957; 147: 258-267Crossref PubMed Google Scholar). We now have considerable knowledge about the biology and biochemistry of the IFN system and the critically important role that IFN plays in the innate immune response (2Samuel C.E. Clin. Microbiol. Rev. 2001; 14: 778-809Crossref PubMed Scopus (2115) Google Scholar). Most recently, exciting progress has been made toward elucidating the biochemical pathways by which the host recognizes invading viral pathogens and triggers the production of the type I IFNs, principally IFN-β. Aspects of the RLR and TLR signaling pathways leading to the induction of type I IFN expression in response to viral nucleic acids are summarized in Fig. 1. The RIG-I-like receptors signal via the mitochondrial membrane-associated interferon promoter stimulator 1 (IPS-1) adaptor protein. The Toll-like receptors signal via either the TRIF (Toll/interleukin 1 receptor domain-containing adaptor protein inducing IFN-β) adaptor protein in the case of TLR3 or the MyD88 (myeloid differentiation primary response protein 88) adaptor protein in the case of TLR7, -8, and -9. These signaling pathways lead to the activation of IRF and NF-κB factors that play a key role in the induction of type I IFN expression.In the first minireview, Mitsutoshi Yoneyama and Takashi Fujita at Kyoto University in their article entitled “Function of RIG-I-like Receptors in Antiviral Innate Immunity” consider new developments in both the biochemistry and biology of the cellular RIG-I helicase family of RNA sensors (3Yoneyama M. Fujita T. J. Biol. Chem. 2007; 282: 15315-15318Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). The functional domains and activities of the RLRs, the nature of the viral RNAs that trigger IFN production in an RLR-dependent manner, the proteins that constitute the RLR signaling pathway, and the antagonism of RLR signaling by viral gene products are discussed.The second minireview of the series by Satoshi Uematsu and Shizuo Akira at Osaka University entitled “Toll-like Receptor and Type I Interferons” focuses on recent developments in understanding the TLR receptors that recognize viral nucleic acids including TLR3, which recognizes dsRNA; TLR7 and TLR8, which recognize G- and U-rich ssRNAs; and TLR9, which recognizes CpG-containing DNA (4Uematsu S. Akira S. J. Biol. Chem. 2007; 282: 15319-15324Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar). In addition, progress in understanding the cell surface recognition of viral envelope components by TLR4 leading to IFN induction is discussed. The roles of the RLRs and individual TLRs are considered in the production of IFN-β and IFN-α in different types of cells, including fibroblasts, conventional dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs).The final minireview of this thematic series on triggers of antiviral innate immunity focuses on the centrally important IRFs involved in transcriptional activation of the type I interferon gene promoters. John Hiscott at McGill University in his minireview entitled “Triggering the Innate Antiviral Response through IRF-3 Activation” describes the role that the transcription factor IRF-3, as well as the closely related factor IRF-7, play in the RLR-dependent and TLR-dependent signaling pathways (5Hiscott J. J. Biol. Chem. 2007; 282: 15325-15329Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar).Much progress has been made in elucidating the biochemical mechanisms by which viral infection causes the transcriptional activation of type I interferon production through the RIG-I-like receptor and Toll-like receptor signaling pathways. The authors and editors hope that this minireview series on antiviral innate immunity will enable researchers in the basic and clinical sciences to better appreciate the signaling pathways and the mechanistic insights gained in the area of viral recognition by RLRs and TLRs leading to the expression of type I interferon genes. An important component of the innate immune response of the host in viral infection is the production of type I interferons. Efforts to understand the molecular mechanisms by which animal viruses and also double-stranded RNA trigger the induction of interferon (IFN) 2The abbreviations used are: IFN, interferon; dsRNA, double-stranded RNA; IRF, interferon regulatory factor; IPS-1, interferon promoter stimulator 1; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; RIG-I, retinoic acid inducible gene I; RLR, RIG-I-like receptor; ssRNA, single-stranded RNA; TLR, Toll-like receptor; TRIF, Toll/interleukin 1 receptor domain-containing adaptor protein inducing interferon.2The abbreviations used are: IFN, interferon; dsRNA, double-stranded RNA; IRF, interferon regulatory factor; IPS-1, interferon promoter stimulator 1; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; RIG-I, retinoic acid inducible gene I; RLR, RIG-I-like receptor; ssRNA, single-stranded RNA; TLR, Toll-like receptor; TRIF, Toll/interleukin 1 receptor domain-containing adaptor protein inducing interferon. have led to the identification of cellular sensors of viral infection. The first two minireviews in this issue provide updates on two kinds of nucleic acid sensors and the biochemical pathways by which they signal the production of interferon. One type of sensor is the family of cytosolic receptor proteins (RIG-I, MDA5, LGP2) known as the retinoic acid-inducible gene I (RIG-I)-like receptors (RLR). The other type of sensor includes members of the Toll-like receptor (TLR) family of cell surface and endosomal membrane protein receptors (TLR3, -7, -8, and -9). These minireviews focus on the biochemical and cellular aspects of the signaling pathways activated by RNA, both single-stranded (ss) RNA and double-stranded (ds) RNA, including the nature of the RLR and TLR sensor proteins and the adaptors through which they signal the production of IFN in virus-infected cells. The third minireview focuses on the structure and function of interferon regulatory factor (IRF) 3 and, to an extent, IRF-7, which are activated by the RLR and TLR signaling pathways. These IRFs, together with the nuclear factor-κB (NF-κB) and activator protein 1 factors lead to the transcriptional activation of the type I interferon β (IFN-β) gene. Interferon was discovered as an antiviral cytokine 50 years ago during seminal studies on virus interference (1Isaacs A. Lindenmann J. Proc. R. Soc. Lond. Ser. B Biol. Sci. 1957; 147: 258-267Crossref PubMed Google Scholar). We now have considerable knowledge about the biology and biochemistry of the IFN system and the critically important role that IFN plays in the innate immune response (2Samuel C.E. Clin. Microbiol. Rev. 2001; 14: 778-809Crossref PubMed Scopus (2115) Google Scholar). Most recently, exciting progress has been made toward elucidating the biochemical pathways by which the host recognizes invading viral pathogens and triggers the production of the type I IFNs, principally IFN-β. Aspects of the RLR and TLR signaling pathways leading to the induction of type I IFN expression in response to viral nucleic acids are summarized in Fig. 1. The RIG-I-like receptors signal via the mitochondrial membrane-associated interferon promoter stimulator 1 (IPS-1) adaptor protein. The Toll-like receptors signal via either the TRIF (Toll/interleukin 1 receptor domain-containing adaptor protein inducing IFN-β) adaptor protein in the case of TLR3 or the MyD88 (myeloid differentiation primary response protein 88) adaptor protein in the case of TLR7, -8, and -9. These signaling pathways lead to the activation of IRF and NF-κB factors that play a key role in the induction of type I IFN expression. In the first minireview, Mitsutoshi Yoneyama and Takashi Fujita at Kyoto University in their article entitled “Function of RIG-I-like Receptors in Antiviral Innate Immunity” consider new developments in both the biochemistry and biology of the cellular RIG-I helicase family of RNA sensors (3Yoneyama M. Fujita T. J. Biol. Chem. 2007; 282: 15315-15318Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). The functional domains and activities of the RLRs, the nature of the viral RNAs that trigger IFN production in an RLR-dependent manner, the proteins that constitute the RLR signaling pathway, and the antagonism of RLR signaling by viral gene products are discussed. The second minireview of the series by Satoshi Uematsu and Shizuo Akira at Osaka University entitled “Toll-like Receptor and Type I Interferons” focuses on recent developments in understanding the TLR receptors that recognize viral nucleic acids including TLR3, which recognizes dsRNA; TLR7 and TLR8, which recognize G- and U-rich ssRNAs; and TLR9, which recognizes CpG-containing DNA (4Uematsu S. Akira S. J. Biol. Chem. 2007; 282: 15319-15324Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar). In addition, progress in understanding the cell surface recognition of viral envelope components by TLR4 leading to IFN induction is discussed. The roles of the RLRs and individual TLRs are considered in the production of IFN-β and IFN-α in different types of cells, including fibroblasts, conventional dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs). The final minireview of this thematic series on triggers of antiviral innate immunity focuses on the centrally important IRFs involved in transcriptional activation of the type I interferon gene promoters. John Hiscott at McGill University in his minireview entitled “Triggering the Innate Antiviral Response through IRF-3 Activation” describes the role that the transcription factor IRF-3, as well as the closely related factor IRF-7, play in the RLR-dependent and TLR-dependent signaling pathways (5Hiscott J. J. Biol. Chem. 2007; 282: 15325-15329Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar). Much progress has been made in elucidating the biochemical mechanisms by which viral infection causes the transcriptional activation of type I interferon production through the RIG-I-like receptor and Toll-like receptor signaling pathways. The authors and editors hope that this minireview series on antiviral innate immunity will enable researchers in the basic and clinical sciences to better appreciate the signaling pathways and the mechanistic insights gained in the area of viral recognition by RLRs and TLRs leading to the expression of type I interferon genes.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.