title: Cellular 5'-3' mRNA exonuclease Xrn1 controls double-stranded RNA accumulation and anti-viral responses.
abstract: By accelerating global mRNA decay, many viruses impair host protein synthesis, limiting host defenses and stimulating virus mRNA translation. Vaccinia virus (VacV) encodes two decapping enzymes (D9, D10) that remove protective 5' caps on mRNAs, presumably generating substrates for degradation by the host exonuclease Xrn1. Surprisingly, we find VacV infection of Xrn1-depleted cells inhibits protein synthesis, compromising virus growth. These effects are aggravated by D9 deficiency and dependent upon a virus transcription factor required for intermediate and late mRNA biogenesis. Considerable double-stranded RNA (dsRNA) accumulation in Xrn1-depleted cells is accompanied by activation of host dsRNA-responsive defenses controlled by PKR and 2'-5' oligoadenylate synthetase (OAS), which respectively inactivate the translation initiation factor eIF2 and stimulate RNA cleavage by RNase L. This proceeds despite VacV-encoded PKR and RNase L antagonists being present. Moreover, Xrn1 depletion sensitizes uninfected cells to dsRNA treatment. Thus, Xrn1 is a cellular factor regulating dsRNA accumulation and dsRNA-responsive innate immune effectors.
authors.affiliation: Department of Microbiology and NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Burgess
authors.affiliation: Department of Microbiology and NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. Electronic address: ian.mohr@med.nyu.edu.
authors.forename: Ian
authors.initials: I
authors.lastname: Mohr
mesh_terms: D002478:Cells, Cultured; D005095:Exoribonucleases / Q000378:metabolism*; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000378:metabolism*; D014616:Vaccinia virus / Q000276:immunology* / Q000502:physiology*; D014779:Virus Replication
chemical_list: D008869:Microtubule-Associated Proteins; D012330:RNA, Double-Stranded; D005095:Exoribonucleases; C470512:XRN1 protein, human