INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation
The evasion of the Interferon response has important implications in Zika virus (ZIKV) disease. Mutations in ZIKV viral protein NS4B, associated with modulation of the interferon (IFN) system, have been linked to increased pathogenicity in animal models. In this study, we unravel ZIKV NS4B as antago...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/13/12/2448 |
| _version_ | 1827668978784272384 |
|---|---|
| author | Elisa Fanunza Nicole Grandi Marina Quartu Fabrizio Carletti Laura Ermellino Jessica Milia Angela Corona Maria Rosaria Capobianchi Giuseppe Ippolito Enzo Tramontano |
| author_facet | Elisa Fanunza Nicole Grandi Marina Quartu Fabrizio Carletti Laura Ermellino Jessica Milia Angela Corona Maria Rosaria Capobianchi Giuseppe Ippolito Enzo Tramontano |
| author_sort | Elisa Fanunza |
| collection | DOAJ |
| description | The evasion of the Interferon response has important implications in Zika virus (ZIKV) disease. Mutations in ZIKV viral protein NS4B, associated with modulation of the interferon (IFN) system, have been linked to increased pathogenicity in animal models. In this study, we unravel ZIKV NS4B as antagonist of the IFN signaling cascade. Firstly, we reported the genomic characterization of NS4B isolated from a strain of the 2016 outbreak, ZIKV Brazil/2016/INMI1, and we predicted its membrane topology. Secondly, we analyzed its phylogenetic correlation with other flaviviruses, finding a high similarity with dengue virus 2 (DEN2) strains; in particular, the highest conservation was found when NS4B was aligned with the IFN inhibitory domain of DEN2 NS4B. Hence, we asked whether ZIKV NS4B was also able to inhibit the IFN signaling cascade, as reported for DEN2 NS4B. Our results showed that ZIKV NS4B was able to strongly inhibit the IFN stimulated response element and the IFN-γ-activated site transcription, blocking IFN-I/-II responses. mRNA expression levels of the IFN stimulated genes <i>ISG15</i> and <i>OAS1</i> were also strongly reduced in presence of NS4B. We found that the viral protein was acting by suppressing the STAT1 phosphorylation and consequently blocking the nuclear transport of both STAT1 and STAT2. |
| first_indexed | 2024-03-10T03:55:08Z |
| format | Article |
| id | doaj.art-5a254e0a899e45f692e15ab1fb872174 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T03:55:08Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-5a254e0a899e45f692e15ab1fb8721742023-11-23T10:58:05ZengMDPI AGViruses1999-49152021-12-011312244810.3390/v13122448INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 PhosphorylationElisa Fanunza0Nicole Grandi1Marina Quartu2Fabrizio Carletti3Laura Ermellino4Jessica Milia5Angela Corona6Maria Rosaria Capobianchi7Giuseppe Ippolito8Enzo Tramontano9Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, ItalyDepartment of Biomedical Sciences, University of Cagliari, 09042 Monserrato, ItalyNational Institute for Infectious Diseases, L. Spallanzani Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), 00149 Rome, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, ItalyNational Institute for Infectious Diseases, L. Spallanzani Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), 00149 Rome, ItalyNational Institute for Infectious Diseases, L. Spallanzani Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), 00149 Rome, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, ItalyThe evasion of the Interferon response has important implications in Zika virus (ZIKV) disease. Mutations in ZIKV viral protein NS4B, associated with modulation of the interferon (IFN) system, have been linked to increased pathogenicity in animal models. In this study, we unravel ZIKV NS4B as antagonist of the IFN signaling cascade. Firstly, we reported the genomic characterization of NS4B isolated from a strain of the 2016 outbreak, ZIKV Brazil/2016/INMI1, and we predicted its membrane topology. Secondly, we analyzed its phylogenetic correlation with other flaviviruses, finding a high similarity with dengue virus 2 (DEN2) strains; in particular, the highest conservation was found when NS4B was aligned with the IFN inhibitory domain of DEN2 NS4B. Hence, we asked whether ZIKV NS4B was also able to inhibit the IFN signaling cascade, as reported for DEN2 NS4B. Our results showed that ZIKV NS4B was able to strongly inhibit the IFN stimulated response element and the IFN-γ-activated site transcription, blocking IFN-I/-II responses. mRNA expression levels of the IFN stimulated genes <i>ISG15</i> and <i>OAS1</i> were also strongly reduced in presence of NS4B. We found that the viral protein was acting by suppressing the STAT1 phosphorylation and consequently blocking the nuclear transport of both STAT1 and STAT2.https://www.mdpi.com/1999-4915/13/12/2448Zika virusinterferoninterferon evasionNS4BSTAT1STAT2 |
| spellingShingle | Elisa Fanunza Nicole Grandi Marina Quartu Fabrizio Carletti Laura Ermellino Jessica Milia Angela Corona Maria Rosaria Capobianchi Giuseppe Ippolito Enzo Tramontano INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation Viruses Zika virus interferon interferon evasion NS4B STAT1 STAT2 |
| title | INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation |
| title_full | INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation |
| title_fullStr | INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation |
| title_full_unstemmed | INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation |
| title_short | INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation |
| title_sort | inmi1 zika virus ns4b antagonizes the interferon signaling by suppressing stat1 phosphorylation |
| topic | Zika virus interferon interferon evasion NS4B STAT1 STAT2 |
| url | https://www.mdpi.com/1999-4915/13/12/2448 |
| work_keys_str_mv | AT elisafanunza inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation AT nicolegrandi inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation AT marinaquartu inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation AT fabriziocarletti inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation AT lauraermellino inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation AT jessicamilia inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation AT angelacorona inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation AT mariarosariacapobianchi inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation AT giuseppeippolito inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation AT enzotramontano inmi1zikavirusns4bantagonizestheinterferonsignalingbysuppressingstat1phosphorylation |