Human Cytomegalovirus IE1 Protein Disrupts Interleukin-6 Signaling by Sequestering STAT3 in the Nucleus

Abstract

In the canonical STAT3 signaling pathway, binding of agonist to receptors activates Janus kinases that phosphorylate cytoplasmic STAT3 at tyrosine 705 (Y705). Phosphorylated STAT3 dimers accumulate in the nucleus and drive the expression of genes involved in inflammation, angiogenesis, invasion, and proliferation. Here, we demonstrate that human cytomegalovirus (HCMV) infection rapidly promotes nuclear localization of STAT3 in the absence of robust phosphorylation at Y705. Furthermore, infection disrupts interleukin-6 (IL-6)-induced phosphorylation of STAT3 and expression of a subset of IL-6-induced STAT3-regulated genes, including SOCS3. We show that the HCMV 72-kDa immediate-early 1 (IE1) protein associates with STAT3 and is necessary to localize STAT3 to the nucleus during infection. Furthermore, expression of IE1 is sufficient to disrupt IL-6-induced phosphorylation of STAT3, binding of STAT3 to the SOCS3 promoter, and SOCS3 gene expression. Finally, inhibition of STAT3 nuclear localization or STAT3 expression during infection is linked to diminished HCMV genome replication. Viral gene expression is also disrupted, with the greatest impact seen following viral DNA synthesis. Our study identifies IE1 as a new regulator of STAT3 intracellular localization and IL-6 signaling and points to an unanticipated role of STAT3 in HCMV infection.

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

“…It was reported that HCMV-infected fibroblasts rapidly accumulate unphosphorylated STAT3 in the nucleus and disrupt IL-6einduced STAT3 activation, events regulated by IE1 protein that diminish viral DNA synthesis and gene expression. 92 In contrast, results of our studies showed that AmEpCs maintain STAT3 activation, which is linked to persistent infection and cell survival.…”

Human Herpesvirus 8 Viral Interleukin-6 Signaling through gp130 Promotes Virus Replication in Primary Effusion Lymphoma and Endothelial Cells

“…For VZV, STAT3-activated survivin was found to be involved in proreplication activity, reflecting the prosurvival activities of STAT3 via survivin reported for PEL cells (24). However, human cytomegalovirus blocks STAT3 phosphorylation, though it requires it for optimal replication, and mouse cytomegalovirus induces phosphorylation of STAT3 but not STAT3-responsive cellular genes, suggesting novel, virus-redirected activities of the transcription factor (37,38). Our findings of vIL-6/gp130 and STAT3 involvement in HHV-8 productive replication could facilitate the development of therapeutic interventions for the treatment of HHV-8-associated diseases, to which productive replication contributes significantly.…”

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

“…Furthermore, HCMV IE1 can promote glioblastoma stemness, cell-cycle progression and survival demonstrating a novel role of IE1 as potent driver for glioblastoma stem-like cells [35] and revealing that HCMV infection might promote pathogenesis in gliomas [36]. In addition, there are studies demonstrating that the IE1 expression increases the proliferation rate in primary glioblastoma cells via the suppression of p53 protein and the activation of Akt signaling [37][38][39] inducing the expression of a negative p53 protein regulator [40]. Beyond, the increase of telomerase activity is also correlated with IE1 gene expression in glioblastoma cell lines while there are reports displaying the co-localization of HCMV IE1 protein with hTERT proteins in gliomas [41].…”