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A human cytomegalovirus antagonist of type I IFN-dependent signal transducer and activator of transcription signaling.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Paulus, Christina Krauss, Steffen Nevels, Michael |
| Copyright Year | 2006 |
| Abstract | Type I IFNs are crucial components of the innate immune response to viral attack. They are rapidly synthesized and secreted after infection with human cytomegalovirus (CMV) and trigger a signal transduction pathway that involves successive activation and nuclear translocation of signal transducer and activator of transcription 1 (STAT1) and STAT2. The activated STATs, together with the IFN regulatory factor 9 protein, form a trimeric transcription complex (IFN-stimulated gene factor 3) that stimulates expression of numerous IFN-responsive genes, many of which exhibit antiviral activity. Here we demonstrate that the viral 72-kDa IE1 protein (IE1-72kDa) confers partial resistance to the antiviral activity of type I IFNs upon CMV. Accordingly, IFN-responsive transcripts accumulate to substantially increased levels after infection with an IE1-deficient mutant as compared with wild-type virus, and ectopic expression of the viral protein in stably transfected cells is sufficient to block their induction. We further show that IE1-72kDa forms a physical complex with STAT1 and STAT2 in nuclei of infected cells and in vitro and prevents association of STAT1, STAT2, and IFN regulatory factor 9 with promoters of IFN-responsive genes in vivo. Our results indicate that the viral protein blocks an intranuclear step after nuclear translocation and before DNA binding of IFN-stimulated gene factor 3, presumably by interfering with the integrity and/or correct subnuclear localization of the protein complex. This study identifies the CMV IE1-72kDa protein as a viral antagonist of the cellular innate immune response, inhibiting IFN-dependent STAT signaling by means of an unprecedented molecular mechanism. |
| Starting Page | 16 |
| Ending Page | 16 |
| Page Count | 1 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.pnas.org/content/103/10/3840.full.pdf |
| PubMed reference number | 16497831v1 |
| Volume Number | 103 |
| Issue Number | 10 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Antiviral Agents Cell secretion Cytomegalovirus Ectopic Gene Expression Immunity, Innate Inhibition Nuclear Translocation STAT protein STAT2 Transcription Factor Signal Transduction Pathways Transcript Transducers Viral Proteins coagulation factor IX, human dna binding peginterferon alfa-2b promoter |
| Content Type | Text |
| Resource Type | Article |
