title: Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1.
abstract: Influenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity.
  
  
  OBJECTIVE
  Influenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN) to block viral replication. Although IAV was shown to have diverse strategies to evade this powerful, IFN-mediated antiviral response, it is not well-defined if IAV manipulates the IFN receptor-mediated signaling pathway. Here, we uncovered that influenza viral hemagglutinin (HA) protein causes the degradation of type I IFN receptor subunit 1 (IFNAR1). HA promoted phosphorylation and polyubiquitination of IFNAR1, which facilitated the degradation of this receptor. The HA-mediated elimination of IFNAR1 notably decreased the cells' sensitivities to type I IFNs, as demonstrated by the diminished expression of IFN-induced antiviral genes. This discovery could help us understand how IAV regulates the host innate immune response to create an environment optimized for viral survival in host cells.
authors.affiliation: Departments of Surgery and Molecular Microbiology & Immunology, University of Missouri, Columbia, Missouri, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Xia
authors.affiliation: Departments of Surgery and Molecular Microbiology & Immunology, University of Missouri, Columbia, Missouri, USA.
authors.forename: Madhuvanthi
authors.initials: M
authors.lastname: Vijayan
authors.affiliation: Departments of Surgery and Molecular Microbiology & Immunology, University of Missouri, Columbia, Missouri, USA.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Pritzl
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Adrian B
authors.initials: AB
authors.lastname: McDermott
authors.affiliation: Departments of Surgery and Molecular Microbiology & Immunology, University of Missouri, Columbia, Missouri, USA hahmb@health.missouri.edu.
authors.forename: Bumsuk
authors.initials: B
authors.lastname: Hahm
mesh_terms: D000818:Animals; D002460:Cell Line; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D009980:Influenza A virus / Q000276:immunology* / Q000502:physiology*; D007370:Interferon Type I / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors*; D054875:Ubiquitination
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; C507964:IFNAR1 protein, human; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta