A human cytomegalovirus antagonist of type I IFN-dependent signal transducer and activator of transcription signaling.
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.
Institut für Medizinische Mikrobiologie und Hygiene, Forschungszentrum, Universität Regensburg, D-93047 Regensburg, Germany.
Christina
C
Paulus
Steffen
S
Krauss
Michael
M
Nevels
D021581:Active Transport, Cell Nucleus; D001483:Base Sequence; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D017874:Immediate-Early Proteins / Q000276:immunology / Q000502:physiology; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014764:Viral Proteins / Q000276:immunology / Q000502:physiology
D002843:Chromatin; D018076:DNA, Complementary; C088645:IE1 protein, cytomegalovirus; C494227:IRF9 protein, human; D017874:Immediate-Early Proteins; D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D014764:Viral Proteins