ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus.
Autophagy-related protein 7 (ATG7) is an essential autophagy effector enzyme. Although it is well known that autophagy plays crucial roles in the infections with various viruses including influenza A virus (IAV), function and underlying mechanism of ATG7 in infection and pathogenesis of IAV remain p...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011958&type=printable |
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| author | Biao Chen Guijie Guo Guoqing Wang Qianwen Zhu Lulu Wang Wenhao Shi Song Wang Yuhai Chen Xiaojuan Chi Faxin Wen Mohamed Maarouf Shile Huang Zhou Yang Ji-Long Chen |
| author_facet | Biao Chen Guijie Guo Guoqing Wang Qianwen Zhu Lulu Wang Wenhao Shi Song Wang Yuhai Chen Xiaojuan Chi Faxin Wen Mohamed Maarouf Shile Huang Zhou Yang Ji-Long Chen |
| author_sort | Biao Chen |
| collection | DOAJ |
| description | Autophagy-related protein 7 (ATG7) is an essential autophagy effector enzyme. Although it is well known that autophagy plays crucial roles in the infections with various viruses including influenza A virus (IAV), function and underlying mechanism of ATG7 in infection and pathogenesis of IAV remain poorly understood. Here, in vitro studies showed that ATG7 had profound effects on replication of IAV. Depletion of ATG7 markedly attenuated the replication of IAV, whereas overexpression of ATG7 facilitated the viral replication. ATG7 conditional knockout mice were further employed and exhibited significantly resistant to viral infections, as evidenced by a lower degree of tissue injury, slower body weight loss, and better survival, than the wild type animals challenged with either IAV (RNA virus) or pseudorabies virus (DNA virus). Interestingly, we found that ATG7 promoted the replication of IAV in autophagy-dependent and -independent manners, as inhibition of autophagy failed to completely block the upregulation of IAV replication by ATG7. To determine the autophagy-independent mechanism, transcriptome analysis was utilized and demonstrated that ATG7 restrained the production of interferons (IFNs). Loss of ATG7 obviously enhanced the expression of type I and III IFNs in ATG7-depleted cells and mice, whereas overexpression of ATG7 impaired the interferon response to IAV infection. Consistently, our experiments demonstrated that ATG7 significantly suppressed IRF3 activation during the IAV infection. Furthermore, we identified long noncoding RNA (lncRNA) GAPLINC as a critical regulator involved in the promotion of IAV replication by ATG7. Importantly, both inactivation of IRF3 and inhibition of IFN response caused by ATG7 were mediated through control over GAPLINC expression, suggesting that GAPLINC contributes to the suppression of antiviral immunity by ATG7. Together, these results uncover an autophagy-independent mechanism by which ATG7 suppresses host innate immunity and establish a critical role for ATG7/GAPLINC/IRF3 axis in regulating IAV infection and pathogenesis. |
| first_indexed | 2024-03-08T04:05:33Z |
| format | Article |
| id | doaj.art-5001d3bbd6a6484aa696146f1732c0ef |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-08T04:05:33Z |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-5001d3bbd6a6484aa696146f1732c0ef2024-02-09T05:30:39ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-01-01201e101195810.1371/journal.ppat.1011958ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus.Biao ChenGuijie GuoGuoqing WangQianwen ZhuLulu WangWenhao ShiSong WangYuhai ChenXiaojuan ChiFaxin WenMohamed MaaroufShile HuangZhou YangJi-Long ChenAutophagy-related protein 7 (ATG7) is an essential autophagy effector enzyme. Although it is well known that autophagy plays crucial roles in the infections with various viruses including influenza A virus (IAV), function and underlying mechanism of ATG7 in infection and pathogenesis of IAV remain poorly understood. Here, in vitro studies showed that ATG7 had profound effects on replication of IAV. Depletion of ATG7 markedly attenuated the replication of IAV, whereas overexpression of ATG7 facilitated the viral replication. ATG7 conditional knockout mice were further employed and exhibited significantly resistant to viral infections, as evidenced by a lower degree of tissue injury, slower body weight loss, and better survival, than the wild type animals challenged with either IAV (RNA virus) or pseudorabies virus (DNA virus). Interestingly, we found that ATG7 promoted the replication of IAV in autophagy-dependent and -independent manners, as inhibition of autophagy failed to completely block the upregulation of IAV replication by ATG7. To determine the autophagy-independent mechanism, transcriptome analysis was utilized and demonstrated that ATG7 restrained the production of interferons (IFNs). Loss of ATG7 obviously enhanced the expression of type I and III IFNs in ATG7-depleted cells and mice, whereas overexpression of ATG7 impaired the interferon response to IAV infection. Consistently, our experiments demonstrated that ATG7 significantly suppressed IRF3 activation during the IAV infection. Furthermore, we identified long noncoding RNA (lncRNA) GAPLINC as a critical regulator involved in the promotion of IAV replication by ATG7. Importantly, both inactivation of IRF3 and inhibition of IFN response caused by ATG7 were mediated through control over GAPLINC expression, suggesting that GAPLINC contributes to the suppression of antiviral immunity by ATG7. Together, these results uncover an autophagy-independent mechanism by which ATG7 suppresses host innate immunity and establish a critical role for ATG7/GAPLINC/IRF3 axis in regulating IAV infection and pathogenesis.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011958&type=printable |
| spellingShingle | Biao Chen Guijie Guo Guoqing Wang Qianwen Zhu Lulu Wang Wenhao Shi Song Wang Yuhai Chen Xiaojuan Chi Faxin Wen Mohamed Maarouf Shile Huang Zhou Yang Ji-Long Chen ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus. PLoS Pathogens |
| title | ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus. |
| title_full | ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus. |
| title_fullStr | ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus. |
| title_full_unstemmed | ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus. |
| title_short | ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus. |
| title_sort | atg7 gaplinc irf3 axis plays a critical role in regulating pathogenesis of influenza a virus |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011958&type=printable |
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