title: Inducible cAMP early repressor (ICER) is a novel regulator of RIG-I mediated IFN-β production.
abstract: Antiviral responses can be triggered by the cytoplasmic RNA helicase RIG-I that binds to viral RNA. RIG-I-mediated signaling stimulates the transcription factors IRF3 and NF-κB and their activation mechanisms have been intensively studied. Here we examined Sendai virus (SV)-mediated activation of the transcription factor CREB and the role of its feedback repressor ICER in production of endogenous antiviral proteins. We show that SV infection and the mitochondrial adapter protein MAVS promote CREB phosphorylation that is dependent upon p38 MAPK and MK2. ICER is induced by CREB and acts as a feedback repressor of CRE-dependent transcription. We found that SV infection stimulated induction of ICER mRNA and protein expression. Surprisingly, ectopic expression and siRNA-mediated knockdown of ICER revealed that ICER is a positive regulator of the production of antiviral IFN-β and IP10 during SV infection. In contrast, ICER did not affect SV-elicited phosphorylation of IRF3, NF-κB or ATF2/c-Jun, transcription factors governing IFN-β and IP10 synthesis. However, expression of ICER increased total IRF3 protein levels during SV infection. These results point to a novel role of ICER in antiviral immune signaling acting to increase levels of antiviral effectors.
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Ingvild.johnsen@ntnu.no
authors.forename: Ingvild Bjellmo
authors.initials: IB
authors.lastname: Johnsen
authors.forename: Bjarte
authors.initials: B
authors.lastname: Bergstroem
authors.forename: Kim A
authors.initials: KA
authors.lastname: Stiberg
authors.forename: Liv
authors.initials: L
authors.lastname: Thommesen
authors.forename: Marit W
authors.initials: MW
authors.lastname: Anthonsen
mesh_terms: D051698:Activating Transcription Factor 2 / Q000276:immunology; D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000242:Cyclic AMP / Q000276:immunology; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000276:immunology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology*; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic; D010253:Respirovirus Infections / Q000235:genetics / Q000276:immunology*; D029082:Sendai virus / Q000502:physiology*; D015533:Transcriptional Activation; D019892:eIF-2 Kinase / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D048868:Adaptor Proteins, Signal Transducing; C497410:CREM protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C505371:MAVS protein, human; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051786:Cyclic AMP Response Element Modulator; D016899:Interferon-beta; D000242:Cyclic AMP; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases