Paulus, Christina and Krauss, Steffen and Nevels, Michael (2006) A human cytomegalovirus antagonist of type IIFN-dependent signal transducer and activator of transcription signaling. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 103 (10). pp. 3840-3845. ISSN 0027-8424,
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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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LOW-MULTIPLICITY INFECTION; IMMEDIATE-EARLY PROTEINS; GENE-EXPRESSION; OLIGONUCLEOTIDE ARRAYS; ANTIVIRAL RESPONSES; VIRAL REPLICATION; GLYCOPROTEIN-B; NUCLEAR-BODIES; JAK-STAT; IE1; herpesvirus; IE1; innate immunity; viral immediate-early protein |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Feb 2021 07:19 |
| Last Modified: | 18 Feb 2021 07:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/34792 |
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