title: Human IFIT1 Inhibits mRNA Translation of Rubulaviruses but Not Other Members of the Paramyxoviridae Family.
abstract: We have previously shown that IFIT1 is primarily responsible for the antiviral action of interferon (IFN) alpha/beta against parainfluenza virus type 5 (PIV5), selectively inhibiting the translation of PIV5 mRNAs. Here we report that while PIV2, PIV5, and mumps virus (MuV) are sensitive to IFIT1, nonrubulavirus members of the paramyxoviridae such as PIV3, Sendai virus (SeV), and canine distemper virus (CDV) are resistant. The IFIT1 sensitivity of PIV5 was not rescued by coinfection with an IFIT1-resistant virus (PIV3), demonstrating that PIV3 does not specifically inhibit the antiviral activity of IFIT1 and that the inhibition of PIV5 mRNAs is regulated by cis-acting elements. We developed an in vitro translation system using purified human IFIT1 to further investigate the mechanism of action of IFIT1. While the translations of PIV2, PIV5, and MuV mRNAs were directly inhibited by IFIT1, the translations of PIV3, SeV, and CDV mRNAs were not. Using purified human mRNA-capping enzymes, we show biochemically that efficient inhibition by IFIT1 is dependent upon a 5' guanosine nucleoside cap (which need not be N7 methylated) and that this sensitivity is partly abrogated by 2'O methylation of the cap 1 ribose. Intriguingly, PIV5 M mRNA, in contrast to NP mRNA, remained sensitive to inhibition by IFIT1 following in vitro 2'O methylation, suggesting that other structural features of mRNAs may influence their sensitivity to IFIT1. Thus, surprisingly, the viral polymerases (which have 2'-O-methyltransferase activity) of rubulaviruses do not protect these viruses from inhibition by IFIT1. Possible biological consequences of this are discussed.
  
  
  
  Paramyxoviruses cause a wide variety of diseases, and yet most of their genes encode structural proteins and proteins involved in their replication cycle. Thus, the amount of genetic information that determines the type of disease that paramyxoviruses cause is relatively small. One factor that will influence disease outcomes is how they interact with innate host cell defenses, including the interferon (IFN) system. Here we show that different paramyxoviruses interact in distinct ways with cells in a preexisting IFN-induced antiviral state. Strikingly, all the rubulaviruses tested were sensitive to the antiviral action of ISG56/IFIT1, while all the other paramyxoviruses tested were resistant. We developed novel in vitro biochemical assays to investigate the mechanism of action of IFIT1, demonstrating that the mRNAs of rubulaviruses can be directly inhibited by IFIT1 and that this is at least partially because their mRNAs are not correctly methylated.
authors: School of Biology, Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife, United Kingdom.
authors: D F
authors: DF
authors: Young
authors: School of Biology, Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife, United Kingdom.
authors: J
authors: J
authors: Andrejeva
authors: Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors: X
authors: X
authors: Li
authors: School of Life Sciences, Centre for Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom.
authors: F
authors: F
authors: Inesta-Vaquera
authors: Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors: C
authors: C
authors: Dong
authors: School of Life Sciences, Centre for Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom.
authors: V H
authors: VH
authors: Cowling
authors: Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom.
authors: S
authors: S
authors: Goodbourn
authors: School of Biology, Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife, United Kingdom rer@st-and.ac.uk.
authors: R E
authors: RE
authors: Randall
mesh_terms: D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D008745:Methylation; D009109:Mumps virus / Q000235:genetics; D045402:Parainfluenza Virus 5 / Q000235:genetics; D010252:Paramyxoviridae / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D012315:RNA Caps / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics; D016601:RNA-Binding Proteins; D019213:Rubulavirus / Q000235:genetics*; D029082:Sendai virus / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C484290:IFIT1 protein, human; D016898:Interferon-alpha; D012315:RNA Caps; D012333:RNA, Messenger; D012367:RNA, Viral; D016601:RNA-Binding Proteins