title: Human Cytomegalovirus Immediate-Early 1 Protein Rewires Upstream STAT3 to Downstream STAT1 Signaling Switching an IL6-Type to an IFNγ-Like Response.
abstract: The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Harwardt
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Lukas
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Zenger
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Reitberger
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Danzer
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Übner
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Munday
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.|Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Michael
authors.identifier: 0000-0002-7115-407X
authors.initials: M
authors.lastname: Nevels
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.|Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Christina
authors.initials: C
authors.lastname: Paulus
mesh_terms: D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism*; D005347:Fibroblasts / Q000821:virology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D016297:Mutagenesis, Site-Directed; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology
chemical_list: C088645:IE1 protein, cytomegalovirus; C508600:IL6 protein, human; D017874:Immediate-Early Proteins; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007371:Interferon-gamma