title: Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I.
abstract: The ubiquitin ligase TRIM25 mediates Lysine 63-linked ubiquitination of the N-terminal CARD domains of the viral RNA sensor RIG-I to facilitate type I interferon (IFN) production and antiviral immunity. Here, we report that the influenza A virus nonstructural protein 1 (NS1) specifically inhibits TRIM25-mediated RIG-I CARD ubiquitination, thereby suppressing RIG-I signal transduction. A novel domain in NS1 comprising E96/E97 residues mediates its interaction with the coiled-coil domain of TRIM25, thus blocking TRIM25 multimerization and RIG-I CARD domain ubiquitination. Furthermore, a recombinant influenza A virus expressing an E96A/E97A NS1 mutant is defective in blocking TRIM25-mediated antiviral IFN response and loses virulence in mice. Our findings reveal a mechanism by which influenza virus inhibits host IFN response and also emphasize the vital role of TRIM25 in modulating antiviral defenses.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Michaela Ulrike
authors.initials: MU
authors.lastname: Gack
authors.forename: Randy Allen
authors.initials: RA
authors.lastname: Albrecht
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Urano
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Inn
authors.forename: I-Chueh
authors.initials: IC
authors.lastname: Huang
authors.forename: Elena
authors.initials: E
authors.lastname: Carnero
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Jae Ung
authors.initials: JU
authors.lastname: Jung
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007251:Influenza, Human / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D007370:Interferon Type I / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011971:Receptors, Immunologic; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C085820:INS1 protein, influenza virus; D007370:Interferon Type I; D011971:Receptors, Immunologic; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D017361:Viral Nonstructural Proteins; C084523:TRIM25 protein, human; D044767:Ubiquitin-Protein Ligases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases