Influenza a virus NS1 resembles a TRAF3-interacting motif to target the RNA sensing-TRAF3-type I IFN axis and impair antiviral innate immunity
Abstract Background Influenza A virus (IAV) evolves strategies to counteract the host antiviral defense for establishing infection. The influenza A virus (IAV) non-structural protein 1 (NS1) is a key viral factor shown to counteract type I IFN antiviral response mainly through targeting RIG-I signal...
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doaj-4827f4362e954f52bfff9b535da068072021-10-10T11:18:51ZengBMCJournal of Biomedical Science1423-01272021-10-0128111710.1186/s12929-021-00764-0Influenza a virus NS1 resembles a TRAF3-interacting motif to target the RNA sensing-TRAF3-type I IFN axis and impair antiviral innate immunityChun-Yang Lin0Meng-Cen Shih1Hung-Chun Chang2Kuan-Jung Lin3Lin-Fang Chen4Sheng-Wen Huang5Mei-Lin Yang6Sheng-Kai Ma7Ai-Li Shiau8Jen-Ren Wang9Kuan-Ru Chen10Pin Ling11Department of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityDepartment of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung UniversityDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityNational Mosquito-Borne Diseases Control Research Center, National Health ResearchDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityDepartment of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung UniversityDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung UniversityAbstract Background Influenza A virus (IAV) evolves strategies to counteract the host antiviral defense for establishing infection. The influenza A virus (IAV) non-structural protein 1 (NS1) is a key viral factor shown to counteract type I IFN antiviral response mainly through targeting RIG-I signaling. Growing evidence suggests that viral RNA sensors RIG-I, TLR3, and TLR7 function to detect IAV RNA in different cell types to induce type I IFN antiviral response to IAV infection. Yet, it remains unclear if IAV NS1 can exploit a common mechanism to counteract these RNA sensing pathways to type I IFN production at once, then promoting viral propagation in the host. Methods Luciferase reporter assays were conducted to determine the effect of NS1 and its mutants on the RIG-I and TLR3 pathways to the activation of the IFN-β and NF-κB promoters. Coimmunoprecipitation and confocal microscopic analyses were used to the interaction and colocalization between NS1 and TRAF3. Ubiquitination assays were performed to study the effect of NS1 and its mutants on TRAF3 ubiquitination. A recombinant mutant virus carrying NS1 E152A/E153A mutations was generated by reverse genetics for biochemical, ex vivo, and in vivo analyses to explore the importance of NS1 E152/E153 residues in targeting the RNA sensing-TRAF3-type I IFN axis and IAV pathogenicity. Results Here we report that NS1 subverts the RIG-I, TLR3, and TLR7 pathways to type I IFN production through targeting TRAF3 E3 ubiquitin ligase. NS1 harbors a conserved FTEE motif (a.a. 150-153), in which the E152/E153 residues are critical for binding TRAF3 to block TRAF3 ubiquitination and type I IFN production by these RNA sensing pathways. A recombinant mutant virus carrying NS1 E152A/E153A mutations induces higher type I IFN production ex vivo and in vivo, and exhibits the attenuated phenotype in infected mice, indicating the importance of E152/E153 residues in IAV pathogenicity. Conclusions Together our work uncovers a novel mechanism of IAV NS1-mediated immune evasion to promote viral infection through targeting the RNA sensing-TRAF3-type I IFN axis.https://doi.org/10.1186/s12929-021-00764-0Influenza virusNS1RIG-ITLR3TLR7Interferon |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chun-Yang Lin Meng-Cen Shih Hung-Chun Chang Kuan-Jung Lin Lin-Fang Chen Sheng-Wen Huang Mei-Lin Yang Sheng-Kai Ma Ai-Li Shiau Jen-Ren Wang Kuan-Ru Chen Pin Ling |
spellingShingle |
Chun-Yang Lin Meng-Cen Shih Hung-Chun Chang Kuan-Jung Lin Lin-Fang Chen Sheng-Wen Huang Mei-Lin Yang Sheng-Kai Ma Ai-Li Shiau Jen-Ren Wang Kuan-Ru Chen Pin Ling Influenza a virus NS1 resembles a TRAF3-interacting motif to target the RNA sensing-TRAF3-type I IFN axis and impair antiviral innate immunity Journal of Biomedical Science Influenza virus NS1 RIG-I TLR3 TLR7 Interferon |
author_facet |
Chun-Yang Lin Meng-Cen Shih Hung-Chun Chang Kuan-Jung Lin Lin-Fang Chen Sheng-Wen Huang Mei-Lin Yang Sheng-Kai Ma Ai-Li Shiau Jen-Ren Wang Kuan-Ru Chen Pin Ling |
author_sort |
Chun-Yang Lin |
title |
Influenza a virus NS1 resembles a TRAF3-interacting motif to target the RNA sensing-TRAF3-type I IFN axis and impair antiviral innate immunity |
title_short |
Influenza a virus NS1 resembles a TRAF3-interacting motif to target the RNA sensing-TRAF3-type I IFN axis and impair antiviral innate immunity |
title_full |
Influenza a virus NS1 resembles a TRAF3-interacting motif to target the RNA sensing-TRAF3-type I IFN axis and impair antiviral innate immunity |
title_fullStr |
Influenza a virus NS1 resembles a TRAF3-interacting motif to target the RNA sensing-TRAF3-type I IFN axis and impair antiviral innate immunity |
title_full_unstemmed |
Influenza a virus NS1 resembles a TRAF3-interacting motif to target the RNA sensing-TRAF3-type I IFN axis and impair antiviral innate immunity |
title_sort |
influenza a virus ns1 resembles a traf3-interacting motif to target the rna sensing-traf3-type i ifn axis and impair antiviral innate immunity |
publisher |
BMC |
series |
Journal of Biomedical Science |
issn |
1423-0127 |
publishDate |
2021-10-01 |
description |
Abstract Background Influenza A virus (IAV) evolves strategies to counteract the host antiviral defense for establishing infection. The influenza A virus (IAV) non-structural protein 1 (NS1) is a key viral factor shown to counteract type I IFN antiviral response mainly through targeting RIG-I signaling. Growing evidence suggests that viral RNA sensors RIG-I, TLR3, and TLR7 function to detect IAV RNA in different cell types to induce type I IFN antiviral response to IAV infection. Yet, it remains unclear if IAV NS1 can exploit a common mechanism to counteract these RNA sensing pathways to type I IFN production at once, then promoting viral propagation in the host. Methods Luciferase reporter assays were conducted to determine the effect of NS1 and its mutants on the RIG-I and TLR3 pathways to the activation of the IFN-β and NF-κB promoters. Coimmunoprecipitation and confocal microscopic analyses were used to the interaction and colocalization between NS1 and TRAF3. Ubiquitination assays were performed to study the effect of NS1 and its mutants on TRAF3 ubiquitination. A recombinant mutant virus carrying NS1 E152A/E153A mutations was generated by reverse genetics for biochemical, ex vivo, and in vivo analyses to explore the importance of NS1 E152/E153 residues in targeting the RNA sensing-TRAF3-type I IFN axis and IAV pathogenicity. Results Here we report that NS1 subverts the RIG-I, TLR3, and TLR7 pathways to type I IFN production through targeting TRAF3 E3 ubiquitin ligase. NS1 harbors a conserved FTEE motif (a.a. 150-153), in which the E152/E153 residues are critical for binding TRAF3 to block TRAF3 ubiquitination and type I IFN production by these RNA sensing pathways. A recombinant mutant virus carrying NS1 E152A/E153A mutations induces higher type I IFN production ex vivo and in vivo, and exhibits the attenuated phenotype in infected mice, indicating the importance of E152/E153 residues in IAV pathogenicity. Conclusions Together our work uncovers a novel mechanism of IAV NS1-mediated immune evasion to promote viral infection through targeting the RNA sensing-TRAF3-type I IFN axis. |
topic |
Influenza virus NS1 RIG-I TLR3 TLR7 Interferon |
url |
https://doi.org/10.1186/s12929-021-00764-0 |
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