title: Rotavirus inhibits IFN-induced STAT nuclear translocation by a mechanism that acts after STAT binding to importin-α.
abstract: The importance of innate immunity to rotaviruses is exemplified by the range of strategies evolved by rotaviruses to interfere with the IFN response. We showed previously that rotaviruses block gene expression induced by type I and II IFNs, through a mechanism allowing activation of signal transducer and activator of transcription (STAT) 1 and STAT2 but preventing their nuclear accumulation. This normally occurs through activated STAT1/2 dimerization, enabling an interaction with importin α5 that mediates transport into the nucleus. In rotavirus-infected cells, STAT1/2 inhibition may limit the antiviral actions of IFN produced early in infection. Here we further analysed the block to STAT1/2 nuclear accumulation, showing that activated STAT1 accumulates in the cytoplasm in rotavirus-infected cells. STAT1/2 nuclear accumulation was inhibited by rotavirus even in the presence of the nuclear export inhibitor Leptomycin B, demonstrating that enhanced nuclear export is not involved in STAT1/2 cytoplasmic retention. The ability to inhibit STAT nuclear translocation was completely conserved amongst the group A rotaviruses tested, including a divergent avian strain. Analysis of mutant rotaviruses indicated that residues after amino acid 47 of NSP1 are dispensable for STAT inhibition. Furthermore, expression of any of the 12 Rhesus monkey rotavirus proteins did not inhibit IFN-stimulated STAT1 nuclear translocation. Finally, co-immunoprecipitation experiments from transfected epithelial cells showed that STAT1/2 binds importin α5 normally following rotavirus infection. These findings demonstrate that rotavirus probably employs a novel strategy to inhibit IFN-induced STAT signalling, which acts after STAT activation and binding to the nuclear import machinery.
authors.affiliation: Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Gavan
authors.initials: G
authors.lastname: Holloway
authors.affiliation: Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Vi T
authors.initials: VT
authors.lastname: Dang
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Jans
authors.affiliation: Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Coulson
mesh_terms: D002460:Cell Line; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007372:Interferons / Q000037:antagonists & inhibitors* / Q000276:immunology; D028884:Karyopherins / Q000378:metabolism; D012401:Rotavirus / Q000276:immunology / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors*; D050795:STAT2 Transcription Factor / Q000037:antagonists & inhibitors*
chemical_list: D028884:Karyopherins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D007372:Interferons