Sequestration by IFIT1 Impairs Translation of 2′O-unmethylated Capped RNA

Habjan, Matthias; Hubel, Philipp; Lacerda, Lívia C. T.; Benda, Christian; Holze, Cathleen; Eberl, H. Christian; Mann, Angelika; Kindler, Eveline; Gil‐Cruz, Cristina; Ziebuhr, John; Thiel, Volker; Pichlmair, Andreas

doi:10.1371/journal.ppat.1003663

Cited by 180 publications

(279 citation 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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“…A large subset of the ISGs has direct antiviral activity through their capacity to block specific steps in the viral life cycle [34]. This includes, for instance, IFIT1, which binds viral 5 0 -triphosphate RNA, thus sequestering the DNA from the eukaryotic translation initiation factors [35,36]. Other ISGs serve to orchestrate the cellular innate immune response.…”

Section: Type I Ifn Responsesmentioning

confidence: 99%

Innate Antiviral Defenses Independent of Inducible IFNα/β Production

Paludan

2016

Trends in Immunology

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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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Sequestration by IFIT1 Impairs Translation of 2′O-unmethylated Capped RNA

Cited by 180 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

Innate Antiviral Defenses Independent of Inducible IFNα/β Production

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

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