tetano
Editor, Senior Moderator
J Biol Chem. 2019 Dec 16. pii: jbc.RA119.011410. doi: 10.1074/jbc.RA119.011410. [Epub ahead of print] [h=1]The influenza NS1 protein modulates RIG-I activation via a strain-specific direct interaction with the second CARD of RIG-I.[/h]
Jureka AS[SUP]1[/SUP], Kleinpeter AB[SUP]1[/SUP], Tipper JL[SUP]1[/SUP], Harrod KS[SUP]1[/SUP], Petit CM[SUP]2[/SUP].
[h=3]Author information[/h] 1 University of Alabama at Birmingham, United States. 2 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, United States.
[h=3]Abstract[/h] A critical role of the influenza A virus non-structural protein 1 (NS1) is to antagonize the host cellular antiviral response. NS1 accomplishes this role through numerous interactions with host proteins including the cytoplasmic pathogen-recognition receptor, retinoic acid inducible gene I (RIG-I). Although the consequences of this interaction have been studied, the complete mechanism by which NS1 antagonizes RIG-I signaling remains unclear. We previously demonstrated that the NS1 RNA binding domain (NS1[SUP]RBD[/SUP]) interacts directly with the second caspase activation and recruitment domain (CARD) of RIG-I. We also identified that a single strain-specific polymorphism in the NS1[SUP]RBD[/SUP] (R21Q) completely abrogates this interaction. Here we investigate the functional consequences of an R21Q mutation on NS1's ability to antagonize RIG-I signaling. We observed that an influenza virus harboring the R21Q mutation in NS1 results in significant upregulation of RIG-I signaling. In support of this, we determined that an R21Q mutation in NS1 results in a marked deficit in NS1's ability to antagonize TRIM25-mediated ubiquitination of the RIG-I CARDs, a critical step in RIG-I activation. We also observed that wild-type NS1 is capable of binding directly to the tandem RIG-I CARDs while the R21Q mutation in NS1 significantly inhibits this interaction. Furthermore, we determined that the R21Q mutation does not impede the interaction between NS1 and TRIM25 nor the NS1[SUP]RBD[/SUP]'s ability to bind RNA. The data presented here offer significant insights into NS1's antagonism of RIG-I and illustrate the importance of understanding the role of strain-specific polymorphisms in the context of this specific NS1 function.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
[h=4]KEYWORDS:[/h] 1918 H1N1; NS1; RIG-I; TRIM25; host-pathogen interaction; infectious disease; influenza; innate immunity; non-structural protein 1; nuclear magnetic resonance (NMR); viral protein
PMID: 31843969 DOI: 10.1074/jbc.RA119.011410
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Jureka AS[SUP]1[/SUP], Kleinpeter AB[SUP]1[/SUP], Tipper JL[SUP]1[/SUP], Harrod KS[SUP]1[/SUP], Petit CM[SUP]2[/SUP].
[h=3]Author information[/h] 1 University of Alabama at Birmingham, United States. 2 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, United States.
[h=3]Abstract[/h] A critical role of the influenza A virus non-structural protein 1 (NS1) is to antagonize the host cellular antiviral response. NS1 accomplishes this role through numerous interactions with host proteins including the cytoplasmic pathogen-recognition receptor, retinoic acid inducible gene I (RIG-I). Although the consequences of this interaction have been studied, the complete mechanism by which NS1 antagonizes RIG-I signaling remains unclear. We previously demonstrated that the NS1 RNA binding domain (NS1[SUP]RBD[/SUP]) interacts directly with the second caspase activation and recruitment domain (CARD) of RIG-I. We also identified that a single strain-specific polymorphism in the NS1[SUP]RBD[/SUP] (R21Q) completely abrogates this interaction. Here we investigate the functional consequences of an R21Q mutation on NS1's ability to antagonize RIG-I signaling. We observed that an influenza virus harboring the R21Q mutation in NS1 results in significant upregulation of RIG-I signaling. In support of this, we determined that an R21Q mutation in NS1 results in a marked deficit in NS1's ability to antagonize TRIM25-mediated ubiquitination of the RIG-I CARDs, a critical step in RIG-I activation. We also observed that wild-type NS1 is capable of binding directly to the tandem RIG-I CARDs while the R21Q mutation in NS1 significantly inhibits this interaction. Furthermore, we determined that the R21Q mutation does not impede the interaction between NS1 and TRIM25 nor the NS1[SUP]RBD[/SUP]'s ability to bind RNA. The data presented here offer significant insights into NS1's antagonism of RIG-I and illustrate the importance of understanding the role of strain-specific polymorphisms in the context of this specific NS1 function.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
[h=4]KEYWORDS:[/h] 1918 H1N1; NS1; RIG-I; TRIM25; host-pathogen interaction; infectious disease; influenza; innate immunity; non-structural protein 1; nuclear magnetic resonance (NMR); viral protein
PMID: 31843969 DOI: 10.1074/jbc.RA119.011410
Free full text