title: The Tudor domain protein Spindlin1 is involved in intrinsic antiviral defense against incoming hepatitis B Virus and herpes simplex virus type 1.
abstract: Hepatitis B virus infection (HBV) is a major risk factor for the development of hepatocellular carcinoma. HBV replicates from a covalently closed circular DNA (cccDNA) that remains as an episome within the nucleus of infected cells and serves as a template for the transcription of HBV RNAs. The regulatory protein HBx has been shown to be essential for cccDNA transcription in the context of infection. Here we identified Spindlin1, a cellular Tudor-domain protein, as an HBx interacting partner. We further demonstrated that Spindlin1 is recruited to the cccDNA and inhibits its transcription in the context of infection. Spindlin1 knockdown induced an increase in HBV transcription and in histone H4K4 trimethylation at the cccDNA, suggesting that Spindlin1 impacts on epigenetic regulation. Spindlin1-induced transcriptional inhibition was greater for the HBV virus deficient for the expression of HBx than for the HBV WT virus, suggesting that HBx counteracts Spindlin1 repression. Importantly, we showed that the repressive role of Spindlin1 is not limited to HBV transcription but also extends to other DNA virus that replicate within the nucleus such as Herpes Simplex Virus type 1 (HSV-1). Taken together our results identify Spindlin1 as a critical component of the intrinsic antiviral defense and shed new light on the function of HBx in HBV infection.
authors.affiliation: Unité des Hépacivirus et Immunité Innée, Institut Pasteur, Paris, France; UMR CNRS 3569, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ducroux
authors.affiliation: Unité des Hépacivirus et Immunité Innée, Institut Pasteur, Paris, France; UMR CNRS 3569, Paris, France.
authors.forename: Shirine
authors.initials: S
authors.lastname: Benhenda
authors.affiliation: Unité des Hépacivirus et Immunité Innée, Institut Pasteur, Paris, France; UMR CNRS 3569, Paris, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Rivière
authors.affiliation: The Leroy T. Canoles Jr Cancer Research Center and Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors.forename: O John
authors.initials: OJ
authors.lastname: Semmes
authors.affiliation: Institut de Génétique Humaine, CNRS UPR 1142, Laboratoire de Virologie Moléculaire, Montpellier, France.
authors.forename: Monsef
authors.initials: M
authors.lastname: Benkirane
authors.affiliation: Unité des Hépacivirus et Immunité Innée, Institut Pasteur, Paris, France; UMR CNRS 3569, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Neuveut
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics; D006509:Hepatitis B / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006515:Hepatitis B virus / Q000502:physiology*; D006561:Herpes Simplex / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D018797:Cell Cycle Proteins; D004279:DNA, Viral; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C104434:spindlin