“Activated” STAT Proteins: A Paradoxical Consequence of Inhibited JAK-STAT Signaling in Cytomegalovirus-Infected Cells

Abstract

We have previously characterized mouse CMV (MCMV)–encoded immune-evasive IFN signaling inhibition and identified the viral protein pM27 as inducer of proteasomal degradation of STAT2. Extending our analysis to STAT1 and STAT3, we found that MCMV infection neither destabilizes STAT1 protein nor prevents STAT1 tyrosine Y701 phosphorylation, nuclear translocation, or the capability to bind γ-activated sequence DNA-enhancer elements. Unexpectedly, the analysis of STAT3 revealed an induction of STAT3 Y705 phosphorylation by MCMV. In parallel, we found decreasing STAT3 protein amounts upon MCMV infection, although STAT3 expression normally is positive autoregulative. STAT3 phosphorylation depended on the duration of MCMV infection, the infectious dose, and MCMV gene expression but was independent of IFNAR1, IL-10, IL-6, and JAK2. Although STAT3 phosphorylation did not require MCMV immediate early 1, pM27, and late gene expression, it was restricted to MCMV-infected cells and not transmitted to bystander cells. Despite intact STAT1 Y701 phosphorylation, IFN-γ–induced target gene transcription (e.g., IRF1 and suppressor of cytokine signaling [SOCS] 1) was strongly impaired. Likewise, the induction of STAT3 target genes (e.g., SOCS3) by IL-6 was also abolished, indicating that MCMV antagonizes STAT1 and STAT3 despite the occurrence of tyrosine phosphorylation. Consistent with the lack of SOCS1 induction, STAT1 phosphorylation was prolonged upon IFN-γ treatment. We conclude that the inhibition of canonical STAT1 and STAT3 target gene expression abrogates their intrinsic negative feedback loops, leading to accumulation of phospho–tyrosine-STAT3 and prolonged STAT1 phosphorylation. These findings challenge the generalization of tyrosine-phosphorylated STATs necessarily being transcriptional active and document antagonistic effects of MCMV on STAT1/3-dependent target gene expression.

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.…”

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

“…Indeed, negative feedback is well established in STAT3 signaling and can exist at many levels. In our mouse models, we may be observing the consequences of negative-feedback inhibition when tonic Stat3 hyperactivation exceeds a threshold, as previously observed (34)(35)(36). Furthermore, STAT3 signaling pathways are subject to significant crosstalk.…”

M27 Expressed by Cytomegalovirus Counteracts Effective Type I Interferon Induction of Myeloid Cells but Not of Plasmacytoid Dendritic Cells

“…Thus, MCMV provides a unique opportunity to study mechanisms that affect the host-pathogen balance. Previous studies showed that MCMV suppressed IFNAR signaling of MCMV-permissive fibroblasts (19,39). Furthermore, other MCMV genes may reduce the induction of IFN-I responses in fibroblasts (21).…”