Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation.
We have investigated the role of signal transducer and activator of transcription (STAT) 2 during human cytomegalovirus (HCMV) replication and found that protein levels of STAT2 are downregulated. STAT2 downregulation was observed in HCMV clinical isolates and laboratory strains with the exception of strain Towne. The HCMV-induced loss of STAT2 protein occurred despite an increased accumulation of STAT2 mRNA; it required HCMV early gene expression. The decrease in STAT2 was sensitive to proteasome inhibition, suggesting degradation of STAT2 via the ubiquitin proteasome pathway. Notably, pUL27, the HCMV homologue of the mouse CMV pM27 protein, which mediates the selective proteolysis of STAT2, did not induce STAT2 downregulation. Moreover, preceding STAT2 degradation, alpha/beta interferon (IFN)-receptor-mediated tyrosine phosphorylation of STAT2 was inhibited in HCMV-infected cells. This effect was paralleled by impaired tyrosine activation of STAT1 and STAT3. Accordingly, IFNs affected the replication efficiency of STAT2 degrading and non-degrading HCMV strains to a similar degree. In summary, HCMV abrogates IFN receptor signalling at multiple checkpoints by independent mechanisms including UL27-independent degradation of STAT2 and a preceding blockade of STAT2 phosphorylation.
Le
Vu Thuy Khanh
VTK
Heinrich-Heine-Universität Düsseldorf, Institut für Virologie, 40225 Düsseldorf, Germany.
Trilling
Mirko
M
Heinrich-Heine-Universität Düsseldorf, Institut für Virologie, 40225 Düsseldorf, Germany.
Wilborn
Manuel
M
Heinrich-Heine-Universität Düsseldorf, Institut für Virologie, 40225 Düsseldorf, Germany.
Hengel
Hartmut
H
Heinrich-Heine-Universität Düsseldorf, Institut für Virologie, 40225 Düsseldorf, Germany.
Zimmermann
Albert
A
Heinrich-Heine-Universität Düsseldorf, Institut für Virologie, 40225 Düsseldorf, Germany.
D000818:Animals; D002460:Cell Line; D003587:Cytomegalovirus / Q000145:classification / Q000472:pathogenicity*; D015536:Down-Regulation; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D013045:Species Specificity; D014443:Tyrosine / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
D007370:Interferon Type I; D050795:STAT2 Transcription Factor; D014764:Viral Proteins; D014443:Tyrosine; D046988:Proteasome Endopeptidase Complex