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.
Influenza virus is a relevant pathogen that causes significant mortality and morbidity in humans. The NS1 protein of this virus is an important virulence factor responsible for evasion of the host antiviral response. Our studies will shed light on the mechanism how the NS1 protein allows influenza virus to avoid cellular recognition and triggering of the antiviral response, an important feature associated with virulence.
|Chen, Chia-Lin; Huang, Jeffrey Y; Wang, Chun-Hsiang et al. (2017) Hepatitis C virus has a genetically determined lymphotropism through co-receptor B7.2. Nat Commun 8:13882|
|Nelson, Emily V; Schmidt, Kristina M; Deflubé, Laure R et al. (2016) Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions. J Virol 90:7268-84|
|Pisanelli, Giuseppe; Laurent-Rolle, Maudry; Manicassamy, Balaji et al. (2016) La Piedad Michoacán Mexico Virus V protein antagonizes type I interferon response by binding STAT2 protein and preventing STATs nuclear translocation. Virus Res 213:11-22|
|Weber, Michaela; Sediri, Hanna; Felgenhauer, Ulrike et al. (2015) Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I. Cell Host Microbe 17:309-19|
|Lee, Jiyoung; Tian, Yongjun; Chan, Stephanie Tze et al. (2015) TNF-? Induced by Hepatitis C Virus via TLR7 and TLR8 in Hepatocytes Supports Interferon Signaling via an Autocrine Mechanism. PLoS Pathog 11:e1004937|
|Zhang, Xianqin; Bogunovic, Dusan; Payelle-Brogard, Béatrice et al. (2015) Human intracellular ISG15 prevents interferon-?/? over-amplification and auto-inflammation. Nature 517:89-93|
|Tian, Y; Kuo, C-F; Sir, D et al. (2015) Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis. Cell Death Differ 22:1025-34|
|Riegger, David; Hai, Rong; Dornfeld, Dominik et al. (2015) The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA. J Virol 89:2241-52|
|Zhang, Jichuan; Fei, Jingyi; Leslie, Benjamin J et al. (2015) Tandem Spinach Array for mRNA Imaging in Living Bacterial Cells. Sci Rep 5:17295|
|Wang, Linya; Tian, Yongjun; Ou, Jing-hsiung James (2015) HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. PLoS Pathog 11:e1004764|
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