title: A new splice variant of the human guanylate-binding protein 3 mediates anti-influenza activity through inhibition of viral transcription and replication.
abstract: Guanylate-binding proteins (GBPs) belong to the family of large GTPases that are induced in response to interferons. GBPs contain an N-terminal globular GTPase domain and a C-terminal α-helical regulatory domain that are connected by a short middle domain. Antiviral activity against vesicular stomatitis virus and encephalomyocarditis virus has been shown for hGBP-1; however, no anti-influenza virus properties for GBPs have been described to date. Here we show that hGBP-1 and hGBP-3 possess anti-influenza viral activity. Furthermore, we have identified a novel splice variant of hGBP-3, named hGBP-3ΔC, with a largely modified C-terminal α-helical domain. While all three GBP isoforms were up-regulated on influenza virus infection, hGBP-3ΔC showed the most prominent antiviral activity in epithelial cells. Mutational analysis of hGBPs revealed that the globular domain is the principal antiviral effector domain, and GTP-binding, but not hydrolysis, is necessary for antiviral action. Furthermore, we showed that hGBP-3ΔC strongly represses the activity of the viral polymerase complex, which results in decreased synthesis of viral vRNA, cRNA, mRNA, and viral proteins, as well.
authors: Institute of Molecular Virology (IMV), Centre for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University, Von-Esmarch-Str. 56, D-48149 Muenster, Germany.
authors: Alexandra
authors: A
authors: Nordmann
authors: Ludmilla
authors: L
authors: Wixler
authors: Yvonne
authors: Y
authors: Boergeling
authors: Viktor
authors: V
authors: Wixler
authors: Stephan
authors: S
authors: Ludwig
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009975:Orthomyxoviridae / Q000235:genetics / Q000276:immunology / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology / Q000502:physiology; D014779:Virus Replication; D014780:Viruses / Q000235:genetics* / Q000276:immunology
chemical_list: D016207:Cytokines; C490287:GBP1 protein, human; C113264:GBP3 protein, human; D020033:Protein Isoforms; D019204:GTP-Binding Proteins