Journal
CELL HOST & MICROBE
Volume 5, Issue 5, Pages 439-449Publisher
CELL PRESS
DOI: 10.1016/j.chom.2009.04.006
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Funding
- NIH [R01 AI46954, U19 Al62623, U54 Al57158]
- CRIP (Center for Research on Influenza Pathogenesis, MAID) [HHSN26620070001, CA082057, CA31363, CA115284, DE019085, RR00168, U19 Al083025]
- MEXT
- Grants-in-Aid for Scientific Research [21591170] Funding Source: KAKEN
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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.
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