Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I.
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.
Gack
Michaela Ulrike
MU
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA.
Albrecht
Randy Allen
RA
Urano
Tomohiko
T
Inn
Kyung-Soo
KS
Huang
I-Chueh
IC
Carnero
Elena
E
Farzan
Michael
M
Inoue
Satoshi
S
Jung
Jae Ung
JU
García-Sastre
Adolfo
A
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*
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