title: Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila.
abstract: In response to infection, the innate immune system rapidly activates an elaborate and tightly orchestrated gene expression program to induce critical antimicrobial genes. While many key players in this program have been identified in disparate biological systems, it is clear that there are additional uncharacterized mechanisms at play. Our previous studies revealed that a rapidly-induced antiviral gene expression program is active against disparate human arthropod-borne viruses in Drosophila. Moreover, one-half of this program is regulated at the level of transcriptional pausing. Here we found that Nup98, a virus-induced gene, was antiviral against a panel of viruses both in cells and adult flies since its depletion significantly enhanced viral infection. Mechanistically, we found that Nup98 promotes antiviral gene expression in Drosophila at the level of transcription. Expression profiling revealed that the virus-induced activation of 36 genes was abrogated upon loss of Nup98; and we found that a subset of these Nup98-dependent genes were antiviral. These Nup98-dependent virus-induced genes are Cdk9-dependent and translation-independent suggesting that these are rapidly induced primary response genes. Biochemically, we demonstrate that Nup98 is directly bound to the promoters of virus-induced genes, and that it promotes occupancy of the initiating form of RNA polymerase II at these promoters, which are rapidly induced on viral infection to restrict human arboviruses in insects.
authors.affiliation: Department of Microbiology.
authors.forename: Debasis
authors.initials: D
authors.lastname: Panda
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: Pau
authors.initials: P
authors.lastname: Pascual-Garcia
authors.affiliation: Department of Bioengineering, and.
authors.forename: Margaret
authors.initials: M
authors.lastname: Dunagin
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tudor
authors.affiliation: Department of Microbiology.
authors.forename: Kaycie C
authors.initials: KC
authors.lastname: Hopkins
authors.affiliation: Department of Microbiology.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Microbiology.
authors.forename: Beth
authors.initials: B
authors.lastname: Gold
authors.affiliation: Department of Bioengineering, and Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Arjun
authors.initials: A
authors.lastname: Raj
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: Maya
authors.initials: M
authors.lastname: Capelson
authors.affiliation: Department of Microbiology, Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, PA 19104 cherrys@mail.med.upenn.edu.
authors.forename: Sara
authors.initials: S
authors.lastname: Cherry
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics* / Q000821:virology*; D005786:Gene Expression Regulation; D017344:Genes, Insect; D006801:Humans; D022022:Nuclear Pore / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport; D012319:RNA Polymerase II / Q000378:metabolism; D012327:RNA Virus Infections / Q000235:genetics* / Q000821:virology*; D012328:RNA Viruses / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012845:Sindbis Virus / Q000502:physiology
chemical_list: D029721:Drosophila Proteins; D028861:Nuclear Pore Complex Proteins; D012333:RNA, Messenger; C000597088:nucleoporin 98, Drosophila; D012319:RNA Polymerase II
keywords: P-TEFb; innate immunity; nuclear pore; nucleoporin; pol II regulation