TRIM mediated host antiviral responses during influenza virus infections

$437,546U19FY2009AINIH

University Of Southern California, Los Angeles CA

Investigators

Linked publications & trials

Paper 35625986 Paper 29321315 Paper 29098213 Paper 28631605 Paper 28067225 Paper 27252530 Paper 26612428 Paper 26546155 Paper 26023919 Paper 25807108 Paper 25704008 Paper 25526090 Paper 25505067 Paper 25453101 Paper 25307056 Paper 25190485 Paper 25084375 Paper 25078692 Paper 25057006 Paper 25033909 Paper 24958845 Paper 24957226 Paper 24882218 Paper 24816846 Paper 24777530 Paper 24743923 Paper 24729742 Paper 24586175 Paper 24528868 Paper 24478431 Paper 24335298 Paper 24333484 Paper 24286188 Paper 24284630 Paper 24257616 Paper 24237697 Paper 24137104 Paper 24056303 Paper 24027317 Paper 23953107 Paper 23921128 Paper 23881501 Paper 23850008 Paper 23846310 Paper 23825951 Paper 23774882 Paper 23772952 Paper 23749635 Paper 23727156 Paper 23722159 Paper 23722158 Paper 23695672 Paper 23686828 Paper 23642014 Paper 23604073 Paper 23601107 Paper 23498958 Paper 23438823 Paper 23328395 Paper 23271971 Paper 23255794 Paper 23251028 Paper 23209422 Paper 23095753 Paper 23091275 Paper 23064150 Paper 23063562 Paper 23056353 Paper 22993153 Paper 22829594 Paper 22797916 Paper 22778433 Paper 22705791 Paper 22677394 Paper 22645314 Paper 22547828 Paper 22542840 Paper 22532680 Paper 22496373 Paper 22466795 Paper 22445226 Paper 22423967 Paper 22423966 Paper 22419161 Paper 22404588 Paper 22398291 Paper 22358840 Paper 22322217 Paper 22320911 Paper 22312003 Paper 22272257 Paper 22207628 Paper 22174864 Paper 22169041 Paper 22105999 Paper 22084075 Paper 22072774 Paper 22027189 Paper 21979817 Paper 21937514

Abstract

The NS1 protein of influenza A virus is a master regulator of the type I IFN-mediated antiviral response induced during viral infection. An important step of this response that is inhibited by this protein is the activation of transcription factors involved in IFN synthesis by the cytoplasmic RNA sensor of viral infection RIG-I. In collaboration with Dr. Jung, overall PI of this U19 proposal, we have found that the NS1 prevents activation of RIG-I by inhibiting its ubiquitination. Specifically, the NS1 binds to and inhibit TRIM25, a cellular ubiquitin ligase that ubiquitinates RIG-I, a process required for RIG-I downstream signaling. Our preliminary evidence also indicates that a mutant influenza A virus expressing an NS1 defective in its ability to bind and inhibit TRIM25 is attenuated and induces more IFN than wild type virus. In our proposed project, we will now investigate in detail the mechanism of inhibition of TRIM25 by the NS1 protein and the functional consequences of this inhibition on the host antiviral response and in the pathogenicity of influenza A virus. Since the NS1 protein has a complex set of nuclear import and export signals regulating its intracellular localization, we will also investigate the relationship between NS1 localization and function, and how NS1 localization is regulated during viral infection. Trafficking studies of NS1 in the cell will be performed with the help of the Imaging Core. These studies will provide us with a better understanding of the suppression of type I IFN induction by influenza virus. Our project will be complemented by Projects 1 and 3, that study the opposite side of the virus-host IFN response, i.e. induction of RIG-I activation;Project 2, that will provide us with structural clues on how RIG-I can be activated/inhibited;and Project 4, that study the impact of a different RNA virus, hepatitis C virus, in the host response, allowing us to compare different mechanisms used by two viruses to evade innate immunity.

View original record on NIH RePORTER →