TY - JOUR
T1 - Influenza A Virus NS1 Targets the Ubiquitin Ligase TRIM25 to Evade Recognition by the Host Viral RNA Sensor RIG-I
AU - Gack, Michaela Ulrike
AU - Albrecht, Randy Allen
AU - Urano, Tomohiko
AU - Inn, Kyung Soo
AU - Huang, I. Chueh
AU - Carnero, Elena
AU - Farzan, Michael
AU - Inoue, Satoshi
AU - Jung, Jae Ung
AU - García-Sastre, Adolfo
N1 - Funding Information:
We wish to thank Richard Cadagan for excellent technical support. We thank Jonathan Yewdell, Savio L.C. Woo, and Luis Martínez-Sobrido for kindly providing the monoclonal NS1 antibody ( Mibayashi et al., 2007 ) VSV-GFP ( Ebert et al., 2003 ), and MDCK-NS1 cell line, respectively. This research was supported in part by grants from the NIH, R01 AI46954, U19 AI62623 (Center for Investigating Viral Immunity and Antagonism), U54 AI57158 (North East Biodefense Center) and by CRIP (Center for Research on Influenza Pathogenesis, NIAID contract HHSN266200700010C) to A.G.-S.; CA082057, CA31363, CA115284, DE019085, and RR00168 to J.U.J; and U19 AI083025 (Center for Immune Mechanisms of Virus Control) to A.G.-S. and J.U.J. This work was further supported by the grant of the Genome Network Project from the MEXT to S.I. and the exchange program between Harvard Medical School and the graduate training program 1071 at the Friedrich-Alexander University Erlangen-Nuremberg, Germany (M.U.G.).
PY - 2009/5/8
Y1 - 2009/5/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/65549164536
U2 - 10.1016/j.chom.2009.04.006
DO - 10.1016/j.chom.2009.04.006
M3 - Article
C2 - 19454348
AN - SCOPUS:65549164536
SN - 1931-3128
VL - 5
SP - 439
EP - 449
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 5
ER -