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Interferon Inducer IFI35 Regulates RIG-I-Mediated Innate Antiviral Response through Mutual Antagonism with Influenza Virus Protein NS1

Influenza A virus (IAV) infection poses a global health threat and is among the most common contagious pathogens to cause severe respiratory infections in humans and animals. ISGs play a key role in host defense against IAV infection. ABSTRACT Interferon-stimulated genes (ISGs) create multiple lines of defense against viral infection. Here, we show that interferon-induced protein 35 (IFI35) inhibits swine (H3N2) influenza virus replication by directly interacting with the viral protein NS1. IFI35 binds more preferentially to the effector domain of NS1 (amino acids 128 to 207 [128-207aa]) than to the viral RNA sensor RIG-I. This promotes mutual antagonism between IFI35 and NS1 and frees RIG-I from IFI35-mediated K48-linked ubiquitination and degradation. However, IFI35 does not interact with the NS1 encoded by avian (H7N9) influenza virus, resulting in IFI35 playing an opposite virus-enabling role during highly pathogenic H7N9 virus infection. Notably, replacing the 128-207aa region of H7N9 NS1 with the corresponding region of H3N2 NS1 results in the chimeric NS1 acquiring the ability to bind to and mutually antagonize IFI35. IFI35-deficient mice accordingly exhibit more resistance to lethal H7N9 infection than exhibited by their wild-type control. Our data uncover a novel mechanism by which IFI35 regulates RIG-I-mediated antiviral immunity through mutual antagonism with influenza virus protein NS1. IMPORTANCE Influenza A virus (IAV) infection poses a global health threat and is among the most common contagious pathogens to cause severe respiratory infections in humans and animals. ISGs play a key role in host defense against IAV infection. In line with others, we show IFI35-mediated ubiquitination of RIG-I to be involved in innate immunity. Moreover, we define a novel role of IFI35 in regulating the type I interferon (IFN) pathway during IAV infection. We found that IFI35 regulates RIG-I-mediated antiviral signaling by interacting with IAV NS1. H3N2 NS1, but notably not H7N9 NS1, interacts with IFI35 and efficiently suppresses IFI35-dependent ubiquitination of RIG-I. IFI35 deficiency protected mice from H7N9 virus infection. Therefore, manipulation of IFI35-NS1 provides a new approach for the development of anti-IAV treatments.