title: Double Plant Homeodomain Fingers 2 (DPF2) Promotes the Immune Escape of Influenza Virus by Suppressing Beta Interferon Production.
abstract: The high mutation rates of the influenza virus genome facilitate the generation of viral escape mutants, rendering vaccines and drugs against influenza virus-encoded targets potentially ineffective. Therefore, we identified host cell determinants dispensable for the host but crucial for virus replication, with the goal of preventing viral escape and finding effective antivirals. To identify these host factors, we screened 2,732 human genes using RNA interference and focused on one of the identified host factors, the double plant homeodomain fingers 2 (DPF2/REQ) gene, for this study. We found that knockdown of DPF2 in cells infected with influenza virus resulted in decreased expression of viral proteins and RNA. Furthermore, production of progeny virus was reduced by two logs in the multiple-cycle growth kinetics assay. We also found that DPF2 was involved in the replication of seasonal influenza A and B viruses. Because DPF2 plays a crucial role in the noncanonical NF-κB pathway, which negatively regulates type I interferon (IFN) induction, we examined the relationship between DPF2 and IFN responses during viral infection. The results showed that knockdown of DPF2 resulted in increased expression of IFN-β and induced phosphorylation of STAT1 in infected cells. In addition, high levels of several cytokines/chemokines (interleukin-8 [IL-8], IP-10, and IL-6) and antiviral proteins (MxA and ISG56) were produced by DPF2 knockdown cells. In conclusion, we identified a novel host factor, DPF2, that is required for influenza virus to evade the host immune response and that may serve as a potential antiviral target.IMPORTANCEInfluenza virus is responsible for seasonal epidemics and occasional pandemics and is an ongoing threat to public health worldwide. Influenza virus relies heavily on cellular factors to complete its life cycle. Here we identified a novel host factor, DPF2, which is involved in influenza virus infection. Our results showed that DPF2 plays a crucial role in the replication and propagation of influenza virus. DPF2 functions in the noncanonical NF-κB pathway, which negatively regulates type I IFN induction. Thus, we investigated the relationship between the IFN response and DPF2 in influenza virus infection. Upon influenza virus infection, DPF2 dysregulated IFN-β induction and expression of cytokines/chemokines and antiviral proteins. This study provides evidence that influenza virus utilizes DPF2 to escape host innate immunity.
authors.affiliation: Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Gyeonggi-do, Republic of Korea.
authors.forename: Dongjo
authors.initials: D
authors.lastname: Shin
authors.affiliation: Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Gyeonggi-do, Republic of Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Lee
authors.affiliation: Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Gyeonggi-do, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, Gyeonggi-do, Republic of Korea jiyoung.min@ip-korea.org.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Min
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D009980:Influenza A virus / Q000254:growth & development / Q000276:immunology / Q000502:physiology*; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology; D007700:Kinetics; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114753:CXCL10 protein, human; C508606:CXCL8 protein, human; D054357:Chemokine CXCL10; D004268:DNA-Binding Proteins; C113581:DPF2 protein, human; C484290:IFIT1 protein, human; C508600:IL6 protein, human; D007370:Interferon Type I; D015850:Interleukin-6; D016209:Interleukin-8; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014157:Transcription Factors; D016899:Interferon-beta
keywords: DPF2; immune escape; influenza virus; interferon