Ifit1 Inhibits Japanese Encephalitis Virus Replication through Binding to 5′ Capped 2′-O Unmethylated RNA

Kimura, Taishi; Katoh, Hiroshi; Kayama, Hisako; Saiga, Hiroyuki; Okuyama, Masatsugu; Okamoto, Tomoyoshi; Umemoto, Eiji; Matsuura, Yoshiharu; Yamamoto, Masahiro

doi:10.1128/jvi.00883-13

Cited by 108 publications

(118 citation statements)

References 45 publications

(76 reference statements)

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“…The four members of the human IFIT family regulate translation by differentially recognizing the 5= termini of their target RNA (28,48). The exact features in the RNA that they recognize is a matter of some debate, but the current consensus is that they bind to 2=-O-unmethylated 5= cap structure (cap 0) and/or 5=-triphosphates (5=-ppp) on the RNA, which are generally absent in cellular mRNA but found in transcripts of intracellular pathogens, such as viruses that lack cap methyltransferase activity and bacteria (62)(63)(64)(65)(66)(67). IFIT1, in particular, shows a high preference for mRNA with unmethylated cap (63-67), whereas IFIT5, which had no inhibitory effect on PIV3, prefers capless, 5=-ppp RNA (67).…”

Section: Discussionmentioning

confidence: 99%

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

Rabbani

Ribaudo

Guo

et al. 2016

J Virol

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A major arm of cellular innate immunity is type I interferon (IFN), represented by IFN-␣ and IFN-␤. Type I IFN transcriptionally induces a large number of cellular genes, collectively known as IFN-stimulated gene (ISG) proteins, which act as antivirals. The IFIT (interferon-induced proteins with tetratricopeptide repeats) family proteins constitute a major subclass of ISG proteins and are characterized by multiple tetratricopeptide repeats (TPRs). In this study, we have interrogated IFIT proteins for the ability to inhibit the growth of human parainfluenza virus type 3 (PIV3), a nonsegmented negative-strand RNA virus of the Paramyxoviridae family and a major cause of respiratory disease in children. We found that IFIT1 significantly inhibited PIV3, whereas IFIT2, IFIT3, and IFIT5 were less effective or not at all. In further screening a set of ISG proteins we discovered that several other such proteins also inhibited PIV3, including IFITM1, IDO (indoleamine 2,3-dioxygenase), PKR (protein kinase, RNA activated), and viperin (virus inhibitory protein, endoplasmic reticulum associated, interferon inducible)/Cig5. The antiviral effect of IDO, the enzyme that catalyzes the first step of tryptophan degradation, could be counteracted by tryptophan. These results advance our knowledge of diverse ISG proteins functioning as antivirals and may provide novel approaches against PIV3. IMPORTANCE The innate immunity of the host, typified by interferon (IFN), is a major antiviral defense. IFN inhibits virus growth by inducing a large number of IFN-stimulated gene (ISG) proteins, several of which have been shown to have specific antiviral functions.Parainfluenza virus type 3 (PIV3) is major pathogen of children, and no reliable vaccine or specific antiviral against it currently exists. In this article, we report several ISG proteins that strongly inhibit PIV3 growth, the use of which may allow a better antiviral regimen targeting PIV3. P arainfluenza virus type 3 (PIV3) is a nonsegmented, negativestrand RNA virus belonging to the Paramyxoviridae family and a major cause of lower respiratory tract infection in humans and cattle (1-3). Human PIV3 is a particularly serious pathogen in young children, second in clinic importance only to respiratory syncytial virus (RSV), another member of the same family (3). There is currently no specific treatment or approved vaccine for PIV3. However, RNA viruses in general, and paramyxoviruses in particular, induce type I interferon (IFN), a major arm of host innate immunity, mainly by activating a cytoplasmic RNA helicase of the RIG-I family, which is followed by a signaling cascade ultimately leading to transcriptional induction of IFN genes (4-6). Early reports showed that PIV3 is highly sensitive to IFN (7), suggesting that this natural antiviral mechanism holds the potential to be harnessed. Type I IFN by itself has no antiviral activity, but upon binding to its cognate receptor on the cell surface, it triggers the so-called IFN response pathway, in which transcription factors STAT...

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Section: Discussionmentioning

confidence: 99%

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

Rabbani

Ribaudo

Guo

et al. 2016

J Virol

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“…Some viruses encode enzymes for 7mGpppN formation and, less frequently, the ribose 2′-O-methylation necessary to generate cap1 (6). Recent studies show that virally encoded cap 2′-O-methyltransferase activity can inhibit the innate immune response (7)(8)(9)(10)(11).…”

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confidence: 99%

“…Recombinant IFIT family proteins range from monomer to multimer, with crystal structures solved for a human IFIT2 homodimer (17), the human IFIT5 monomer (16,18,19), and an N-terminal fragment of human IFIT1 (18). Studies of IFIT1 report its preferential binding to either 5′ triphosphate (ppp) RNA (15) or cap0 RNA (11,20) or optimally cap0 without guanosine N7-methylation (10). Reports of IFIT5 RNA binding specificity are likewise inconsistent: the protein has been described to bind RNA single-stranded 5′ ends with ppp and monophosphate (p) but not OH (16); ppp but not p, OH, or cap0 (18); ppp but not cap0 (10, 20); or single-stranded 5′-p RNA and double-stranded DNA (19).…”

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confidence: 99%

Broad and adaptable RNA structure recognition by the human interferon-induced tetratricopeptide repeat protein IFIT5

Katibah

Qin

Sidote

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

118

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Interferon (IFN) responses play key roles in cellular defense against pathogens. Highly expressed IFN-induced proteins with tetratricopeptide repeats (IFITs) are proposed to function as RNA binding proteins, but the RNA binding and discrimination specificities of IFIT proteins remain unclear. Here we show that human IFIT5 has comparable affinity for RNAs with diverse phosphate-containing 5′-ends, excluding the higher eukaryotic mRNA cap. Systematic mutagenesis revealed that sequence substitutions in IFIT5 can alternatively expand or introduce bias in protein binding to RNAs with 5′ monophosphate, triphosphate, cap0 (triphosphate-bridged N7-methylguanosine), or cap1 (cap0 with RNA 2′-O-methylation). We defined the breadth of cellular ligands for IFIT5 by using a thermostable group II intron reverse transcriptase for RNA sequencing. We show that IFIT5 binds precursor and processed tRNAs, as well as other RNA polymerase III transcripts. Our findings establish the RNA recognition specificity of the human innate immune response protein IFIT5.innate immunity | poly-U tailing | protein-RNA interaction | RNA post-transcriptional modifications | tRNA processing I nnate immune responses provide a front-line defense against pathogens. Unlike adaptive immune responses, innate immunity relies on general principles of discrimination between self and pathogen epitopes to trigger pathogen suppression (1). Pathogen-specific features that can provide this discrimination come under evolutionary selection to evade host detection, and in turn, host genes adapt new recognition specificities for pathogen signatures. Among the most clearly established targets of innate immune response recognition are nucleic acid structures not typical of the host cell, such as cytoplasmic double-stranded RNA (2). Detection of a pathogen nucleic acid signature robustly induces type I IFN, which activates a cascade of pathways for producing antiviral effectors (3).Cytoplasmic viral RNA synthesis occurs without cotranscriptional coupling to the 5′-capping machinery, which acts pervasively on host cell nuclear RNA polymerase II transcripts (4, 5). Eukaryotic mRNA 5′ ends are first modified by addition of a cap0 structure containing N7-methylated guanosine, which is joined to the first nucleotide (nt) of RNA by a 5′-5′ triphosphate linkage (7mGpppN). In higher eukaryotes including humans, cap0 is further modified by ribose 2′-O-methylation of at least 1 nt (7mGpppNm, cap1) and sometimes 2 nt (7mGpppNmpNm, cap2). Cap0 addition makes essential contributions to mRNA biogenesis and function in steps of mRNA splicing, translation, and protection from decay (4, 5). In contrast, the biological role of mRNA cap0 modification to cap1 and cap2 structures is largely enigmatic. Some viruses encode enzymes for 7mGpppN formation and, less frequently, the ribose 2′-O-methylation necessary to generate cap1 (6). Recent studies show that virally encoded cap 2′-O-methyltransferase activity can inhibit the innate immune response (7-11).The IFN-induced protein with tetratricop...

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“…On the other hand, 2=-O MTase-defective WNV, MHV, and vaccinia virus were more sensitive to antiviral inhibition by IFN-inducible protein with tetratricopeptide repeats (IFITs), which are interferon-stimulated genes (ISGs) linked to translational regulation (56). It was also found that IFIT1 directly binds to the capped RNA and that this binding was dependent on the methylation state of the cap (57). Specifically, the binding of IFIT1 to 2=-O-unmethylated capped RNA impairs the recruitment of eukaryotic translation initiation factors to the 2=-O-unmethylated RNA template, thereby selectively inhibiting viral RNA translation.…”

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confidence: 91%

Methyltransferase-Defective Avian Metapneumovirus Vaccines Provide Complete Protection against Challenge with the Homologous Colorado Strain and the Heterologous Minnesota Strain

Sun¹,

Wei²,

Rauf³

et al. 2014

J Virol

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Avian metapneumovirus (aMPV), also known as avian pneumovirus or turkey rhinotracheitis virus, is the causative agent of turkey rhinotracheitis and is associated with swollen head syndrome in chickens. Since its discovery in the 1970s, aMPV has been recognized as an economically important pathogen in the poultry industry worldwide. The conserved region VI (CR VI) of the large (L) polymerase proteins of paramyxoviruses catalyzes methyltransferase (MTase) activities that typically methylate viral mRNAs at guanine N-7 (G-N-7) and ribose 2=-O positions. In this study, we generated a panel of recombinant aMPV (raMPV) Colorado strains carrying mutations in the S-adenosyl methionine (SAM) binding site in the CR VI of L protein. These recombinant viruses were specifically defective in ribose 2=-O, but not G-N-7 methylation and were genetically stable and highly attenuated in cell culture and viral replication in the upper and lower respiratory tracts of specific-pathogen-free (SPF) young turkeys. Importantly, turkeys vaccinated with these MTase-defective raMPVs triggered a high level of neutralizing antibody and were completely protected from challenge with homologous aMPV Colorado strain and heterologous aMPV Minnesota strain. Collectively, our results indicate (i) that aMPV lacking 2=-O methylation is highly attenuated in vitro and in vivo and (ii) that inhibition of mRNA cap MTase can serve as a novel target to rationally design live attenuated vaccines for aMPV and perhaps other paramyxoviruses. IMPORTANCE Paramyxoviruses include many economically and agriculturally important viruses such as avian metapneumovirus (aMPV), andNewcastle disease virus (NDV), human pathogens such as human respiratory syncytial virus, human metapneumovirus, human parainfluenza virus type 3, and measles virus, and highly lethal emerging pathogens such as Nipah virus and Hendra virus. For many of them, there is no effective vaccine or antiviral drug. These viruses share common strategies for viral gene expression and replication. During transcription, paramyxoviruses produce capped, methylated, and polyadenylated mRNAs. Using aMPV as a model, we found that viral ribose 2=-O methyltransferase (MTase) is a novel approach to rationally attenuate the virus for vaccine purpose. Recombinant aMPV (raMPV) lacking 2=-O MTase were not only highly attenuated in turkeys but also provided complete protection against the challenge of homologous and heterologous aMPV strains. This novel approach can be applicable to other animal and human paramyxoviruses for rationally designing live attenuated vaccines.

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Ifit1 Inhibits Japanese Encephalitis Virus Replication through Binding to 5′ Capped 2′-O Unmethylated RNA

Cited by 108 publications

References 45 publications

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

Broad and adaptable RNA structure recognition by the human interferon-induced tetratricopeptide repeat protein IFIT5

Methyltransferase-Defective Avian Metapneumovirus Vaccines Provide Complete Protection against Challenge with the Homologous Colorado Strain and the Heterologous Minnesota Strain

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