title: IQGAP2 is a novel interferon-alpha antiviral effector gene acting non-conventionally through the NF-κB pathway.
abstract: Type I interferons (IFN) provide the first line of defense against invading pathogens but its mechanism of action is still not well understood. Using unbiased genome-wide siRNA screens, we recently identified IQ-motif containing GTPase activating protein 2 (IQGAP2), a tumor suppressor predominantly expressed in the liver, as a novel gene putatively required for IFN antiviral response against hepatitis C virus (HCV) infection. Here we sought to characterize IQGAP2 role in IFN response.
  
  
  
  We used transient small interfering RNA knockdown strategy in hepatic cell lines highly permissive to JFH1 strain of HCV infection.
  
  
  
  We found that IQGAP2 acts downstream of IFN binding to its receptor, and independently of the JAK-STAT pathway, by physically interacting with RelA (also known as p65), a subunit of the NF-κB transcription factor. Interestingly, our data reveal a mechanism distinct from the well-characterized role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in IFN production. Indeed, IFN alone was sufficient to stimulate NF-κB-dependent transcription in the absence of viral infection. Finally, both IQGAP2 and RelA were required for the induction by IFN of a subset of IFN-stimulated genes (ISG) with known antiviral properties.
  
  
  
  Our data identify a novel function for IQGAP2 in IFN antiviral response in hepatoma cells. We demonstrate the involvement of IQGAP2 in regulating ISG induction by IFN in an NF-κB-dependent manner. The IQGAP2 pathway may provide new targets for antiviral strategies in the liver, and may have a wider therapeutic implication in other disease pathogeneses driven by NF-κB activation.
  
  
  
  In this study, we identify a novel mechanism of action of interferon involving the IQGAP2 protein and the NF-κB pathway that is ultimately protective against hepatitis C virus infection. This newly identified pathway functions independently of the well-known STAT pathway and may therefore provide new targets for antiviral strategies in the liver.
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Brisac
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Shadi
authors.initials: S
authors.lastname: Salloum
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Yang
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Esperance A K
authors.initials: EA
authors.lastname: Schaefer
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jacinta A
authors.initials: JA
authors.lastname: Holmes
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Virology, INSERM U955, Hôpital Henri Mondor, Creteil, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Chevaliez
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Hong
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Charlie
authors.initials: C
authors.lastname: Carlton-Smith
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Alatrakchi
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Kruger
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Lin
authors.affiliation: Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: rtchung@partners.org.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
mesh_terms: D000998:Antiviral Agents; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D016898:Interferon-alpha; D016328:NF-kappa B; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; C101002:IQGAP2 protein, human; D016898:Interferon-alpha; D016328:NF-kappa B; D020703:ras GTPase-Activating Proteins
keywords: Antiviral response; Hepatitis C virus (HCV); IQGAP protein