KRT6A Restricts Influenza A Virus Replication by Inhibiting the Nuclear Import and Assembly of Viral Ribonucleoprotein Complex
The transcription and replication of the genome of influenza A virus (IAV) take place in the nucleus of infected cells, which is catalyzed by the viral ribonucleoprotein (vRNP) complex. The nuclear import of the vRNP complex and its component proteins is essential for the efficient replication of IA...
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| author | Yu Chang Zhibo Shan Wenjun Shi Qibing Li Yihan Wang Bo Wang Guangwen Wang Hualan Chen Li Jiang Chengjun Li |
| author_facet | Yu Chang Zhibo Shan Wenjun Shi Qibing Li Yihan Wang Bo Wang Guangwen Wang Hualan Chen Li Jiang Chengjun Li |
| author_sort | Yu Chang |
| collection | DOAJ |
| description | The transcription and replication of the genome of influenza A virus (IAV) take place in the nucleus of infected cells, which is catalyzed by the viral ribonucleoprotein (vRNP) complex. The nuclear import of the vRNP complex and its component proteins is essential for the efficient replication of IAV and is therefore prone to be targeted by host restriction factors. Herein, we found that host cellular protein keratin 6A (KRT6A) is a negative regulator of IAV replication because siRNA-mediated knockdown of <i>KRT6A</i> expression increased the growth titers of IAV, whereas exogenous overexpression of KRT6A reduced viral yields. The nuclear import of incoming vRNP complexes and newly synthesized nucleoprotein (NP) was significantly impaired when KRT6A was overexpressed. Further studies showed that KRT6A interacts with the four vRNP complex proteins—polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), polymerase acidic protein (PA), and NP. Notably, the interaction between KRT6A and vRNP complex proteins had no effect on the nuclear import of PB2 or the PB1-PA heterodimer but impaired the interaction between NP and the nuclear import adaptor importin α3, thereby inhibiting the nuclear import of incoming vRNP complexes and newly synthesized NP. Moreover, KRT6A was further shown to suppress the assembly of the vRNP complex and consequently reduce viral polymerase activity. Together, our data uncover a novel role of KRT6A in counteracting the nuclear import and functions of the vRNP complex, thereby restricting the replication of IAV. |
| format | Article |
| id | doaj-art-e8463b8252e644bdb411d9bb1bea72bb |
| institution | OA Journals |
| issn | 1999-4915 |
| language | English |
| publishDate | 2025-05-01 |
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| series | Viruses |
| spelling | doaj-art-e8463b8252e644bdb411d9bb1bea72bb2025-08-20T01:56:39ZengMDPI AGViruses1999-49152025-05-0117567110.3390/v17050671KRT6A Restricts Influenza A Virus Replication by Inhibiting the Nuclear Import and Assembly of Viral Ribonucleoprotein ComplexYu Chang0Zhibo Shan1Wenjun Shi2Qibing Li3Yihan Wang4Bo Wang5Guangwen Wang6Hualan Chen7Li Jiang8Chengjun Li9State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, ChinaState Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, ChinaTechnology Center of Qingdao Customs, Qingdao 266000, ChinaState Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, ChinaState Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, ChinaState Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, ChinaState Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, ChinaState Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, ChinaState Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, ChinaState Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, ChinaThe transcription and replication of the genome of influenza A virus (IAV) take place in the nucleus of infected cells, which is catalyzed by the viral ribonucleoprotein (vRNP) complex. The nuclear import of the vRNP complex and its component proteins is essential for the efficient replication of IAV and is therefore prone to be targeted by host restriction factors. Herein, we found that host cellular protein keratin 6A (KRT6A) is a negative regulator of IAV replication because siRNA-mediated knockdown of <i>KRT6A</i> expression increased the growth titers of IAV, whereas exogenous overexpression of KRT6A reduced viral yields. The nuclear import of incoming vRNP complexes and newly synthesized nucleoprotein (NP) was significantly impaired when KRT6A was overexpressed. Further studies showed that KRT6A interacts with the four vRNP complex proteins—polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), polymerase acidic protein (PA), and NP. Notably, the interaction between KRT6A and vRNP complex proteins had no effect on the nuclear import of PB2 or the PB1-PA heterodimer but impaired the interaction between NP and the nuclear import adaptor importin α3, thereby inhibiting the nuclear import of incoming vRNP complexes and newly synthesized NP. Moreover, KRT6A was further shown to suppress the assembly of the vRNP complex and consequently reduce viral polymerase activity. Together, our data uncover a novel role of KRT6A in counteracting the nuclear import and functions of the vRNP complex, thereby restricting the replication of IAV.https://www.mdpi.com/1999-4915/17/5/671influenza A virusKRT6AvRNP complexNPnuclear importassembly |
| spellingShingle | Yu Chang Zhibo Shan Wenjun Shi Qibing Li Yihan Wang Bo Wang Guangwen Wang Hualan Chen Li Jiang Chengjun Li KRT6A Restricts Influenza A Virus Replication by Inhibiting the Nuclear Import and Assembly of Viral Ribonucleoprotein Complex Viruses influenza A virus KRT6A vRNP complex NP nuclear import assembly |
| title | KRT6A Restricts Influenza A Virus Replication by Inhibiting the Nuclear Import and Assembly of Viral Ribonucleoprotein Complex |
| title_full | KRT6A Restricts Influenza A Virus Replication by Inhibiting the Nuclear Import and Assembly of Viral Ribonucleoprotein Complex |
| title_fullStr | KRT6A Restricts Influenza A Virus Replication by Inhibiting the Nuclear Import and Assembly of Viral Ribonucleoprotein Complex |
| title_full_unstemmed | KRT6A Restricts Influenza A Virus Replication by Inhibiting the Nuclear Import and Assembly of Viral Ribonucleoprotein Complex |
| title_short | KRT6A Restricts Influenza A Virus Replication by Inhibiting the Nuclear Import and Assembly of Viral Ribonucleoprotein Complex |
| title_sort | krt6a restricts influenza a virus replication by inhibiting the nuclear import and assembly of viral ribonucleoprotein complex |
| topic | influenza A virus KRT6A vRNP complex NP nuclear import assembly |
| url | https://www.mdpi.com/1999-4915/17/5/671 |
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