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.
Highlights
Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways are the principal means by which responses to dozens of cytokines, growth factors and other extracellular molecules are transduced from the cell surface to the nucleus
Our previous work has shown that the human cytomegalovirus major immediate-early 1 protein (IE1) modulates host cell signaling pathways involving proteins of the signal transducer and activator of transcription (STAT) family
In this report we demonstrate that IE1 is as significant a repressor as it is an activator of host gene expression
Summary
Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways are the principal means by which responses to dozens of cytokines, growth factors and other extracellular molecules are transduced from the cell surface to the nucleus. The ligand-receptor interaction is followed by dimerization of the IL6 signal transducer (IL6Rβ, GP130 or IL6ST) subunits common to all IL6 family cytokine receptors. JAK1 is phosphorylated and the activated kinase subsequently phosphorylates tyrosine residues in the cytoplasmic tail of IL6ST. These phosphotyrosines serve as docking sites for the src homology 2 (SH2) domain of cytoplasmic STAT3. The active pSTAT3 dimers subsequently dissociate from the receptor and accumulate in the nucleus, most likely coordinate with their ability to bind DNA [5]. DNA binding occurs rather sequence-resulting in transcriptional activation of select target genes involved in diverse processes including cell survival and proliferation [1, 6, 7]. One of the pSTAT3 target genes encodes the suppressor of cytokine signaling 3 (SOCS3) which forms part of a negative feedback circuit by inhibiting IL6 signaling [8, 9]
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