SRSF5‐Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host‐Directed Target Against Influenza Virus
Abstract Splicing of influenza A virus (IAV) RNA is an essential process in the viral life cycle that involves the co‐opting of host factors. Here, it is demonstrated that induction of host serine and arginine‐rich splicing factor 5 (SRSF5) by IAV facilitated viral replication by enhancing viral M m...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-12-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202203088 |
| _version_ | 1811301590917709824 |
|---|---|
| author | Qiuchen Li Zhimin Jiang Shuning Ren Hui Guo Zhimin Song Saini Chen Xintao Gao Fanfeng Meng Junda Zhu Litao Liu Qi Tong Honglei Sun Yipeng Sun Juan Pu Kin‐Chow Chang Jinhua Liu |
| author_facet | Qiuchen Li Zhimin Jiang Shuning Ren Hui Guo Zhimin Song Saini Chen Xintao Gao Fanfeng Meng Junda Zhu Litao Liu Qi Tong Honglei Sun Yipeng Sun Juan Pu Kin‐Chow Chang Jinhua Liu |
| author_sort | Qiuchen Li |
| collection | DOAJ |
| description | Abstract Splicing of influenza A virus (IAV) RNA is an essential process in the viral life cycle that involves the co‐opting of host factors. Here, it is demonstrated that induction of host serine and arginine‐rich splicing factor 5 (SRSF5) by IAV facilitated viral replication by enhancing viral M mRNA splicing. Mechanistically, SRSF5 with its RRM2 domain directly bounds M mRNA at conserved sites (M mRNA position 163, 709, and 712), and interacts with U1 small nuclear ribonucleoprotein (snRNP) to promote M mRNA splicing and M2 production. Mutations introduced to the three binding sites, without changing amino acid code, significantly attenuates virus replication and pathogenesis in vivo. Likewise, SRSF5 conditional knockout in the lung protects mice against lethal IAV challenge. Furthermore, anidulafungin, an approved antifungal drug, is identified as an inhibitor of SRSF5 that effectively blocks IAV replication in vitro and in vivo. In conclusion, SRSF5 as an activator of M mRNA splicing promotes IAV replication and is a host‐derived antiviral target. |
| first_indexed | 2024-04-13T07:11:19Z |
| format | Article |
| id | doaj.art-84f94975c1714d73af23c92062e3eb55 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-13T07:11:19Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-84f94975c1714d73af23c92062e3eb552022-12-22T02:56:52ZengWileyAdvanced Science2198-38442022-12-01934n/an/a10.1002/advs.202203088SRSF5‐Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host‐Directed Target Against Influenza VirusQiuchen Li0Zhimin Jiang1Shuning Ren2Hui Guo3Zhimin Song4Saini Chen5Xintao Gao6Fanfeng Meng7Junda Zhu8Litao Liu9Qi Tong10Honglei Sun11Yipeng Sun12Juan Pu13Kin‐Chow Chang14Jinhua Liu15Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaChinese Academy of Sciences Key Laboratory of Infection and Immunity Institute of Biophysics Chinese Academy of Sciences Beijing 100101 ChinaChinese Academy of Sciences Key Laboratory of Infection and Immunity Institute of Biophysics Chinese Academy of Sciences Beijing 100101 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaBiotechnology Research Institute Chinese Academy of Agricultural Sciences Beijing 100081 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaSchool of Veterinary Medicine and Science University of Nottingham Sutton Bonington Campus Sutton Bonington LE12 5RD UKKey Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases Key Laboratory of Animal Epidemiology Ministry of Agriculture College of Veterinary Medicine China Agricultural University Beijing 100193 ChinaAbstract Splicing of influenza A virus (IAV) RNA is an essential process in the viral life cycle that involves the co‐opting of host factors. Here, it is demonstrated that induction of host serine and arginine‐rich splicing factor 5 (SRSF5) by IAV facilitated viral replication by enhancing viral M mRNA splicing. Mechanistically, SRSF5 with its RRM2 domain directly bounds M mRNA at conserved sites (M mRNA position 163, 709, and 712), and interacts with U1 small nuclear ribonucleoprotein (snRNP) to promote M mRNA splicing and M2 production. Mutations introduced to the three binding sites, without changing amino acid code, significantly attenuates virus replication and pathogenesis in vivo. Likewise, SRSF5 conditional knockout in the lung protects mice against lethal IAV challenge. Furthermore, anidulafungin, an approved antifungal drug, is identified as an inhibitor of SRSF5 that effectively blocks IAV replication in vitro and in vivo. In conclusion, SRSF5 as an activator of M mRNA splicing promotes IAV replication and is a host‐derived antiviral target.https://doi.org/10.1002/advs.202203088alternative splicinganidulafungininfluenza A virusesSRSF5U1 snRNP |
| spellingShingle | Qiuchen Li Zhimin Jiang Shuning Ren Hui Guo Zhimin Song Saini Chen Xintao Gao Fanfeng Meng Junda Zhu Litao Liu Qi Tong Honglei Sun Yipeng Sun Juan Pu Kin‐Chow Chang Jinhua Liu SRSF5‐Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host‐Directed Target Against Influenza Virus Advanced Science alternative splicing anidulafungin influenza A viruses SRSF5 U1 snRNP |
| title | SRSF5‐Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host‐Directed Target Against Influenza Virus |
| title_full | SRSF5‐Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host‐Directed Target Against Influenza Virus |
| title_fullStr | SRSF5‐Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host‐Directed Target Against Influenza Virus |
| title_full_unstemmed | SRSF5‐Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host‐Directed Target Against Influenza Virus |
| title_short | SRSF5‐Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host‐Directed Target Against Influenza Virus |
| title_sort | srsf5 mediated alternative splicing of m gene is essential for influenza a virus replication a host directed target against influenza virus |
| topic | alternative splicing anidulafungin influenza A viruses SRSF5 U1 snRNP |
| url | https://doi.org/10.1002/advs.202203088 |
| work_keys_str_mv | AT qiuchenli srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT zhiminjiang srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT shuningren srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT huiguo srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT zhiminsong srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT sainichen srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT xintaogao srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT fanfengmeng srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT jundazhu srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT litaoliu srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT qitong srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT hongleisun srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT yipengsun srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT juanpu srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT kinchowchang srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus AT jinhualiu srsf5mediatedalternativesplicingofmgeneisessentialforinfluenzaavirusreplicationahostdirectedtargetagainstinfluenzavirus |