Interferon-inducible protein, P56, inhibits HPV DNA replication by binding to the viral protein E1.
Type I interferon (IFN) inhibits, by an unknown mechanism, the replication of human papillomaviruses (HPV), which are major human pathogens, Here, we present evidence that P56 (a protein), the expression of which is strongly induced by IFN, double-stranded RNA and viruses, mediates the anti-HPV effect of IFN. Ectopic expression of P56 inhibited HPV DNA replication and its ablation in IFN-treated cells alleviated the inhibitory effect of IFN on HPV DNA replication. Protein-protein interaction and mutational analyses established that the antiviral effect of P56 was mediated by its direct interaction with the DNA replication origin-binding protein E1 of several strains of HPV, through the tetratricopeptide repeat 2 in the N-terminal region of P56 and the C-terminal region of E1. In vivo, the interaction with P56, a cytoplasmic protein, caused translocation of E1 from the nucleus to the cytoplasm. In vitro, recombinant P56, or a small fragment derived from it, inhibited the DNA helicase activity of E1 and E1-mediated HPV DNA replication. These observations delineate the molecular mechanism of IFN's antiviral action against HPV.
Terenzi
Fulvia
F
Department of Molecular Genetics, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Saikia
Paramananda
P
Sen
Ganes C
GC
D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D004252:DNA Mutational Analysis; D004261:DNA Replication; D006801:Humans; D007372:Interferons / Q000276:immunology*; D016297:Mutagenesis, Site-Directed; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors*; D027383:Papillomaviridae / Q000502:physiology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D021381:Protein Transport; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C484290:IFIT1 protein, human; D009856:Oncogene Proteins, Viral; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C084762:oncogene protein E1, Human papillomavirus type 18; D007372:Interferons