Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication.
Dengue virus (DENV) is one of the most important arthropod-borne pathogens that cause life-threatening diseases in humans. However, no vaccine or specific antiviral is available for dengue. As seen in other RNA viruses, the innate immune system plays a key role in controlling DENV infection and dise...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1005357 |
| _version_ | 1818582046786715648 |
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| author | Youichi Suzuki Wei-Xin Chin Qi'En Han Koji Ichiyama Ching Hua Lee Zhi Wen Eyo Hirotaka Ebina Hirotaka Takahashi Chikako Takahashi Beng Hui Tan Takayuki Hishiki Kenji Ohba Toshifumi Matsuyama Yoshio Koyanagi Yee-Joo Tan Tatsuya Sawasaki Justin Jang Hann Chu Subhash G Vasudevan Kouichi Sano Naoki Yamamoto |
| author_facet | Youichi Suzuki Wei-Xin Chin Qi'En Han Koji Ichiyama Ching Hua Lee Zhi Wen Eyo Hirotaka Ebina Hirotaka Takahashi Chikako Takahashi Beng Hui Tan Takayuki Hishiki Kenji Ohba Toshifumi Matsuyama Yoshio Koyanagi Yee-Joo Tan Tatsuya Sawasaki Justin Jang Hann Chu Subhash G Vasudevan Kouichi Sano Naoki Yamamoto |
| author_sort | Youichi Suzuki |
| collection | DOAJ |
| description | Dengue virus (DENV) is one of the most important arthropod-borne pathogens that cause life-threatening diseases in humans. However, no vaccine or specific antiviral is available for dengue. As seen in other RNA viruses, the innate immune system plays a key role in controlling DENV infection and disease outcome. Although the interferon (IFN) response, which is central to host protective immunity, has been reported to limit DENV replication, the molecular details of how DENV infection is modulated by IFN treatment are elusive. In this study, by employing a gain-of-function screen using a type I IFN-treated cell-derived cDNA library, we identified a previously uncharacterized gene, C19orf66, as an IFN-stimulated gene (ISG) that inhibits DENV replication, which we named Repressor of yield of DENV (RyDEN). Overexpression and gene knockdown experiments revealed that expression of RyDEN confers resistance to all serotypes of DENV in human cells. RyDEN expression also limited the replication of hepatitis C virus, Kunjin virus, Chikungunya virus, herpes simplex virus type 1, and human adenovirus. Importantly, RyDEN was considered to be a crucial effector molecule in the IFN-mediated anti-DENV response. When affinity purification-mass spectrometry analysis was performed, RyDEN was revealed to form a complex with cellular mRNA-binding proteins, poly(A)-binding protein cytoplasmic 1 (PABPC1), and La motif-related protein 1 (LARP1). Interestingly, PABPC1 and LARP1 were found to be positive modulators of DENV replication. Since RyDEN influenced intracellular events on DENV replication and, suppression of protein synthesis from DENV-based reporter construct RNA was also observed in RyDEN-expressing cells, our data suggest that RyDEN is likely to interfere with the translation of DENV via interaction with viral RNA and cellular mRNA-binding proteins, resulting in the inhibition of virus replication in infected cells. |
| first_indexed | 2024-12-16T07:43:10Z |
| format | Article |
| id | doaj.art-79f23a7e69834ebb9890be7671e8e272 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-16T07:43:10Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-79f23a7e69834ebb9890be7671e8e2722022-12-21T22:39:03ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742016-01-01121e100535710.1371/journal.ppat.1005357Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication.Youichi SuzukiWei-Xin ChinQi'En HanKoji IchiyamaChing Hua LeeZhi Wen EyoHirotaka EbinaHirotaka TakahashiChikako TakahashiBeng Hui TanTakayuki HishikiKenji OhbaToshifumi MatsuyamaYoshio KoyanagiYee-Joo TanTatsuya SawasakiJustin Jang Hann ChuSubhash G VasudevanKouichi SanoNaoki YamamotoDengue virus (DENV) is one of the most important arthropod-borne pathogens that cause life-threatening diseases in humans. However, no vaccine or specific antiviral is available for dengue. As seen in other RNA viruses, the innate immune system plays a key role in controlling DENV infection and disease outcome. Although the interferon (IFN) response, which is central to host protective immunity, has been reported to limit DENV replication, the molecular details of how DENV infection is modulated by IFN treatment are elusive. In this study, by employing a gain-of-function screen using a type I IFN-treated cell-derived cDNA library, we identified a previously uncharacterized gene, C19orf66, as an IFN-stimulated gene (ISG) that inhibits DENV replication, which we named Repressor of yield of DENV (RyDEN). Overexpression and gene knockdown experiments revealed that expression of RyDEN confers resistance to all serotypes of DENV in human cells. RyDEN expression also limited the replication of hepatitis C virus, Kunjin virus, Chikungunya virus, herpes simplex virus type 1, and human adenovirus. Importantly, RyDEN was considered to be a crucial effector molecule in the IFN-mediated anti-DENV response. When affinity purification-mass spectrometry analysis was performed, RyDEN was revealed to form a complex with cellular mRNA-binding proteins, poly(A)-binding protein cytoplasmic 1 (PABPC1), and La motif-related protein 1 (LARP1). Interestingly, PABPC1 and LARP1 were found to be positive modulators of DENV replication. Since RyDEN influenced intracellular events on DENV replication and, suppression of protein synthesis from DENV-based reporter construct RNA was also observed in RyDEN-expressing cells, our data suggest that RyDEN is likely to interfere with the translation of DENV via interaction with viral RNA and cellular mRNA-binding proteins, resulting in the inhibition of virus replication in infected cells.https://doi.org/10.1371/journal.ppat.1005357 |
| spellingShingle | Youichi Suzuki Wei-Xin Chin Qi'En Han Koji Ichiyama Ching Hua Lee Zhi Wen Eyo Hirotaka Ebina Hirotaka Takahashi Chikako Takahashi Beng Hui Tan Takayuki Hishiki Kenji Ohba Toshifumi Matsuyama Yoshio Koyanagi Yee-Joo Tan Tatsuya Sawasaki Justin Jang Hann Chu Subhash G Vasudevan Kouichi Sano Naoki Yamamoto Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication. PLoS Pathogens |
| title | Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication. |
| title_full | Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication. |
| title_fullStr | Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication. |
| title_full_unstemmed | Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication. |
| title_short | Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication. |
| title_sort | characterization of ryden c19orf66 as an interferon stimulated cellular inhibitor against dengue virus replication |
| url | https://doi.org/10.1371/journal.ppat.1005357 |
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