Hypersusceptibility to vesicular stomatitis virus infection in Dicer1-deficient mice is due to impaired miR24 and miR93 expression.

Dicer is essential for plant, Caenorhabditis elegans, and Drosophila antiviral responses because of its role in generating small interfering RNA (siRNA) from viral genomes. We show that because of impaired miRNA production, mice with a variant Dicer1 allele (Dicer1(d/d)) were more susceptible to vesicular stomatitis virus (VSV) infection. We did not detect VSV genome-derived siRNA in wild-type cells or any alteration of interferon-mediated antiviral responses by Dicer1 deficiency. Rather, we found that host miR24 and miR93 could target viral large protein (L protein) and phosphoprotein (P protein) genes, and a lack of miR24 and miR93 was responsible for increased VSV replication in Dicer1(d/d) cells. Our data suggest that host miRNA can play a role in host interactions with viruses.

[1]  Pascal Barbry,et al.  Suppression of MicroRNA-Silencing Pathway by HIV-1 During Virus Replication , 2007, Science.

[2]  Jinsong Bao,et al.  Hierarchical Action and Inhibition of Plant Dicer-Like Proteins in Antiviral Defense , 2006, Science.

[3]  G. Hannon,et al.  RNase III enzymes and the initiation of gene silencing , 2004, Nature Structural &Molecular Biology.

[4]  Subash Das,et al.  The Latent Membrane Protein 1 of Epstein-Barr Virus Establishes an Antiviral State via Induction of Interferon-stimulated Genes* , 2004, Journal of Biological Chemistry.

[5]  S. Elledge,et al.  Dicer is essential for mouse development , 2003, Nature Genetics.

[6]  Zhengfan Jiang,et al.  CD14 is required for MyD88-independent LPS signaling , 2005, Nature Immunology.

[7]  Vesselin Baev,et al.  MicroInspector: a web tool for detection of miRNA binding sites in an RNA sequence , 2005, Nucleic Acids Res..

[8]  M. Whitt,et al.  Recombinant vesicular stomatitis viruses from DNA. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  P. Sarnow,et al.  Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA , 2005, Science.

[10]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[11]  E. Sontheimer,et al.  Distinct Roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA Silencing Pathways , 2004, Cell.

[12]  Edwards Allen,et al.  DICER-LIKE 4 functions in trans-acting small interfering RNA biogenesis and vegetative phase change in Arabidopsis thaliana. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  T. Tuschl,et al.  Mechanisms of gene silencing by double-stranded RNA , 2004, Nature.

[14]  Olivier Voinnet,et al.  Induction and suppression of RNA silencing: insights from viral infections , 2005, Nature Reviews Genetics.

[15]  A. Pasquinelli,et al.  Genes and Mechanisms Related to RNA Interference Regulate Expression of the Small Temporal RNAs that Control C. elegans Developmental Timing , 2001, Cell.

[16]  F. J. Livesey,et al.  A role for Dicer in immune regulation , 2006, The Journal of experimental medicine.

[17]  Khaled Machaca,et al.  RNA interference is an antiviral defence mechanism in Caenorhabditis elegans , 2005, Nature.

[18]  Y. Shiratori,et al.  Hepatitis C Virus Core Protein Enhances p53 Function through Augmentation of DNA Binding Affinity and Transcriptional Ability* , 2000, The Journal of Biological Chemistry.

[19]  G. Sen,et al.  Inhibition of vesicular stomatitis viral mRNA synthesis by interferons , 1987, Journal of virology.

[20]  Shuang Huang,et al.  Involvement of MicroRNA in AU-Rich Element-Mediated mRNA Instability , 2005, Cell.

[21]  David Baltimore,et al.  MicroRNA-155 is induced during the macrophage inflammatory response , 2007, Proceedings of the National Academy of Sciences.

[22]  Morris F. Maduro,et al.  Animal virus replication and RNAi-mediated antiviral silencing in Caenorhabditis elegans , 2005, Nature.

[23]  G. Hannon,et al.  The miRNA-Processing Enzyme Dicer Is Essential for the Morphogenesis and Maintenance of Hair Follicles , 2006, Current Biology.

[24]  B. Cullen.  Viruses and microRNAs , 2006, Nature Genetics.

[25]  A. García-Sastre,et al.  VIRUSES AND THE TYPE I INTERFERON ANTIVIRAL SYSTEM: INDUCTION AND EVASION , 2002, International reviews of immunology.

[26]  Kaoru Saigo,et al.  Short-Interfering-RNA-Mediated Gene Silencing in Mammalian Cells Requires Dicer and eIF2C Translation Initiation Factors , 2003, Current Biology.

[27]  C. Sander,et al.  Identification of microRNAs of the herpesvirus family , 2005, Nature Methods.

[28]  A. Saïb,et al.  A Cellular MicroRNA Mediates Antiviral Defense in Human Cells , 2005, Science.

[29]  F. Dietrich,et al.  Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs , 2006, Nature Genetics.

[30]  G. Hannon.  RNA interference : RNA , 2002 .

[31]  Michael T. McManus,et al.  The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Ranit Aharonov,et al.  MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. , 2004, Genome research.

[33]  A. Pattnaik,et al.  Phosphorylation of Vesicular Stomatitis Virus Phosphoprotein P Is Indispensable for Virus Growth , 2004, Journal of Virology.

[34]  George E. Sandusky,et al.  Dicer Is Required for Embryonic Angiogenesis during Mouse Development* , 2005, Journal of Biological Chemistry.

[35]  S. Whelan,et al.  An antiviral role for the RNA interference machinery in Caenorhabditis elegans. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Matthias Merkenschlager,et al.  T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer , 2005, The Journal of experimental medicine.

[37]  J. Messing,et al.  CARPEL FACTORY, a Dicer Homolog, and HEN1, a Novel Protein, Act in microRNA Metabolism in Arabidopsis thaliana , 2002, Current Biology.

[38]  A. Schneemann,et al.  Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila , 2006, Nature Immunology.

[39]  A. Hatzigeorgiou,et al.  A combined computational-experimental approach predicts human microRNA targets. , 2004, Genes & development.

[40]  Adam M. Gustafson,et al.  Genetic and Functional Diversification of Small RNA Pathways in Plants , 2004, PLoS biology.

[41]  A. García-Sastre,et al.  Inhibition of the Type I Interferon Response by the Nucleoprotein of the Prototypic Arenavirus Lymphocytic Choriomeningitis Virus , 2006, Journal of Virology.

[42]  Jiahuai Han,et al.  Resistance to Tumor Necrosis Factor-Induced Cell Death Mediated by PMCA4 Deficiency , 2001, Molecular and Cellular Biology.

[43]  Michael T. McManus,et al.  Dicer function is essential for lung epithelium morphogenesis , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[44]  K. Rajewsky,et al.  Aberrant T cell differentiation in the absence of Dicer , 2005, The Journal of experimental medicine.

[45]  W. Stanford,et al.  Gene-trap mutagenesis: past, present and beyond , 2001, Nature Reviews Genetics.

[46]  R. Carthew,et al.  Methods and Materials , 1956, Eco-Art Therapy in Practice.